Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

ABSTRACT

The present invention relates to pharmaceutical formulations comprising at least one acid-labile proton pump inhibiting agent and at least one antacid, which have improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. The present invention is directed to methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease, or the symptoms associated with, or related to, a gastrointestinal disorder or disease in a subject in need thereof.

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/138,763, filed on May 25, 2005, which in turn claims benefitunder 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/574,646,filed May 25, 2004 and U.S. Provisional Application No. 60/574,663,filed May 25, 2004, the contents of each of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations in solidoral dosage form comprising at least one acid-labile proton pumpinhibiting agent and at least one antacid, which have improvedbioavailability, chemical stability, physical stability, dissolutionprofiles, disintegration times, safety, as well as other improvedpharmacokinetic, pharmacodynamic, chemical and/or physical properties.Also described herein are pharmaceutical formulations comprising atleast one proton pump inhibiting agent and about 5 mEq to about 11 mEqof antacid, which have similar bioavailability, chemical stability,physical stability, dissolution profiles, disintegration times, safety,as well as other improved pharmacokinetic, pharmacodynamic, chemicaland/or physical properties to similar combinations comprising greaterthan 11 mEq of antacid.

The present invention is directed to methods, kits, combinations, andcompositions for treating, preventing or reducing the risk of developinga gastrointestinal disorder or disease, or the symptoms associated with,or related to, a gastrointestinal disorder or disease in a subject inneed thereof.

BACKGROUND OF THE INVENTION

Upon ingestion, most acid-labile pharmaceutical compounds must beprotected from contact with acidic stomach secretions to maintain theirpharmaceutical activity. To accomplish this, compositions withenteric-coatings have been designed to dissolve at a neutral pH toensure that the drug is released in the proximal region of the smallintestine (duodenum), rather than the acidic environment of the stomach.However, due to the pH-dependent attributes of these enteric-coatedcompositions and the uncertainty of gastric retention time, in-vivoperformance as well as both inter- and intra-subject variability are allmajor set backs of using enteric-coated systems for the controlledrelease of a drug.

In addition, Phillips et al. has described non-enteric coatedpharmaceutical compositions. These compositions, which allow for theimmediate release of the pharmaceutically active ingredient into thestomach, involve the administration of one or more antacids with an acidlabile pharmaceutical agent, such as a proton pump inhibitor. Theantacid is thought to prevent substantial degradation of the acid labilepharmaceutical agent in the acidic environment of the stomach by raisingthe pH. See, e.g., U.S. Pat. Nos. 5,840,737 and 6,489,346.

A class of acid-labile pharmaceutical compounds that are administered asenteric-coated dosage forms are proton pump inhibiting agents. Exemplaryproton pump inhibitors include: omeprazole (Prilosec®), lansoprazole(Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®),pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole.The drugs of this class suppress gastrointestinal acid secretion by thespecific inhibition of the H⁺/K⁺-ATPase enzyme system (proton pump) atthe secretory surface of the gastrointestinal parietal cell. Most protonpump inhibitors are susceptible to acid degradation and, as such, arerapidly destroyed as pH falls to an acidic level. Therefore, if theenteric-coating of these formulated products is disrupted (e.g.,trituration to compound a liquid, or chewing the capsule or tablet) orthe antacid fails to sufficiently neutralize the gastrointestinal pH,the drug will be exposed to degradation by the gastrointestinal acid inthe stomach.

Omeprazole is one example of a proton pump inhibitor which is asubstituted bicyclic aryl-imidazole,5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,that inhibits gastrointestinal acid secretion. U.S. Pat. No. 4,786,505to Lovgren et al. teaches that a pharmaceutical oral solid dosage formof omeprazole must be protected from contact with acidicgastrointestinal juice by an enteric-coating to maintain itspharmaceutical activity and describes an enteric-coated omeprazolepreparation containing one or more subcoats between the core materialand the enteric-coating.

Proton pump inhibitors are typically prescribed for short-term treatmentof active duodenal ulcers, gastrointestinal ulcers, gastro esophagealreflux disease (GERD), severe erosive esophagitis, poorly responsivesymptomatic GERD, and pathological hypersecretory conditions such asZollinger Ellison syndrome. These above-listed conditions commonly arisein healthy or critically ill patients of all ages, and may beaccompanied by significant upper gastrointestinal bleeding.

It is believed that omeprazole, lansoprazole and other proton pumpinhibiting agents reduce gastrointestinal acid production by inhibitingH⁺/K⁺-ATPase of the parietal cell the final common pathway forgastrointestinal acid secretion. See, e.g., Fellenius et al.,Substituted Benzimidazoles Inhibit Gastrointestinal Acid Secretion byBlocking H⁺/K⁺-ATPase, Nature, 290: 159-161 (1981); Wallmark et al., TheRelationship Between Gastrointestinal Acid Secretion andGastrointestinal H⁺/K⁺-ATPase Activity, J. Biol. Chem., 260: 13681-13684(1985); and Fryklund et al., Function and Structure of Parietal CellsAfter H⁺/K⁺-ATPase Blockade, Am. J. Physiol., 254 (1988).

Proton pump inhibitors have the ability to act as weak bases that reachparietal cells from the blood and diffuse into the secretory canaliculi.There, the drugs become protonated and thereby trapped. The protonatedcompound can then rearrange to form a sulfenamide, which can covalentlyinteract with sulfhydryl groups at critical sites in the extra cellular(luminal) domain of the membrane-spanning H⁺/K⁺-ATPase. See, e.g.,Hardman et al., Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 907 (9th ed. 1996). As such, proton pump inhibitors areprodrugs that must be activated to be effective. The specificity of theeffects of proton pump inhibiting agents is also dependent upon: (a) theselective distribution of H⁺/K⁺-ATPase; (b) the requirement for acidicconditions to catalyze generation of the reactive inhibitor; and (c) thetrapping of the protonated drug and the cationic sulfenamide within theacidic canaliculi and adjacent to the target enzyme. See, e.g., Hardmanet al.

SUMMARY OF THE INVENTION

The present invention is directed to pharmaceutical formulations in asolid oral dosage form comprising (a) at least one acid-labile protonpump inhibitor, and (b) at least one antacid sufficient to increasegastric pH to a pH that prevents acid degradation of at least some ofthe proton pump inhibitor in the gastric fluid, wherein upon oraladministration to a patient, a therapeutically effective amount of theproton pump inhibitor is delivered and T_(max) of the proton pumpinhibitor is obtained within about 75 minutes after administration. Inalternative embodiments, T_(max) of the proton pump inhibitor isobtained within about 60 minutes, or within about 45 minutes, or withinabout 30 minutes after administration. In some embodiments, the solidoral dosage form is a capsule. In other embodiments, the solid oraldosage form is a caplet.

In one embodiment, pharmaceutical formulations in a solid oral dosageform comprising (a) at least one acid-labile proton pump inhibitor; (b)a sufficient amount of sodium bicarbonate to increase gastric fluid pHto a pH that prevents acid degradation of at least some of the protonpump inhibitor in the gastric fluid; and (c) less than about 3% ofdisintegrant, wherein upon oral administration to a patient atherapeutically effective amount of the proton pump inhibitor isdelivered and T_(max) of the proton pump inhibitor is obtained withinabout 75 minutes after administration are described. In otherembodiments, the pharmaceutical formulations comprise less than about 2%or less than about 1% of disintegrant. In alternative embodiments,T_(max) of the proton pump inhibitor is obtained within about 60minutes, or within about 45 minutes, or within about 30 minutes afteradministration. In some embodiments, the solid oral dosage form is acapsule. In other embodiments, the solid oral dosage form is a caplet.

Stable pharmaceutical formulations in a solid oral dosage formcomprising (a) at least one acid-labile proton pump inhibitor, and (b)at least one antacid in an amount sufficient to increase gastric fluidpH to a pH that prevents acid degradation of at least some of the protonpump inhibitor in the gastric fluid, wherein the pharmaceuticalformulation does not comprise a binder; and wherein upon oraladministration to a patient: a therapeutically effective amount of theproton pump inhibitor is delivered and T_(max) of the proton pumpinhibitor is obtained within about 75 minutes after administration arealso provided herein. In some embodiments, the antacid is present in anamount of greater than about 5 mEqs. In other embodiments, the antacidis present in an amount of about 5 mEq to about 30 mEq, or about 5 mEqto about 20 mEq, or about 8 mEq to about 15 mEq, or about 10 mEq toabout 15 mEq. In still other embodiments, the antacid is present in anamount of about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq,or about 9 mEq, or about 10 mEq, or about 11 mEq, or about 12 mEq, orabout 13 mEq, or about 14 mEq, or about 15 mEq, or about 16 mEq, orabout 17 mEq, or about 18 mEq, or about 19 mEq, or about 20 mEq, orabout 22.5 mEq, or about 25 mEq, or about 27 mEq, or about 30 mEq, orabout 35 mEq. In some embodiments, the solid oral dosage form is acapsule. In other embodiments, the solid oral dosage form is a caplet.

Stable pharmaceutical formulations in a solid oral dosage formcomprising (a) at least one acid-labile proton pump inhibitor, (b) atleast about 5 mEq of antacid, wherein the antacid is a combination of atleast two different antacids, and (c) between about 3% to about 11% of adisintegrant, wherein upon oral administration to a patient atherapeutically effective amount of the proton pump inhibitor isdelivered and T_(max) of the proton pump inhibitor is obtained withinabout 75 minutes, are also provided herein. In some embodiments thepharmaceutical formulation comprises about 4% to about 8% disintegrant.In other embodiments, the pharmaceutical formulation comprises about 5%to about 7% disintegrant. In alternative embodiments, T_(max) of theproton pump inhibitor is obtained within about 60 minutes, or withinabout 45 minutes, or within about 30 minutes after administration. Insome embodiments, the solid oral dosage form is a capsule. In otherembodiments, the solid oral dosage form is a caplet.

Also provided herein are stable pharmaceutical formulations in a singlecapsule dosage form comprising (a) at least one acid-labile proton pumpinhibitor, (b) about 5 to about 15 mEq of sodium bicarbonate, and (c)less than about 3% of a disintegrant, wherein upon oral administrationto a patient a therapeutically effective amount of the proton pumpinhibitor is delivered and T_(max) of the proton pump inhibitor isobtained within about 75 minutes. In some embodiments, thepharmaceutical formulation comprises about 8 mEq to about 15 mEq ofsodium bicarbonate. In other embodiments, the pharmaceutical formulationcomprises about 10 mEq to about 15 mEq of sodium bicarbonate. In yetother embodiments, the pharmaceutical formulation comprises about 13 mEqof sodium bicarbonate. In still other embodiments, T_(max) of the protonpump inhibitor is obtained within about 60 minutes, or within about 45minutes, or within about 30 minutes after administration.

Stable pharmaceutical formulations in a solid oral dosage formcomprising (a) omeprazole or a salt, hydrate, ester, amide, enantiomer,isomer, tautomer, polymorph, or prodrug thereof, (b) at least about 5mEq of sodium bicarbonate, and (c) less than about 3% of a disintegrant,wherein the pharmaceutical formulation does not comprise a binder; andwherein upon oral administration to a patient a therapeuticallyeffective amount of the proton pump inhibitor is delivered and T_(max)of the proton pump inhibitor is obtained within about 75 minutes afteradministration are also provided herein. In some embodiments, thepharmaceutical formulation comprises between about 5 mEq to about 20mEq, or between about 5 mEq to about 15 mEq, or between about 10 mEq toabout 15 mEq of sodium bicarbonate. In other embodiments, thepharmaceutical formulation comprises less than about 2% sodiumbicarbonate. In yet other embodiments, T_(max) of the proton pumpinhibitor is obtained within about 60 minutes, or within about 45minutes, or within about 30 minutes after administration. In someembodiments, the solid oral dosage form is a capsule. In otherembodiments, the solid oral dosage form is a caplet.

Also provided herein are stable pharmaceutical formulations in singlecapsule dosage form comprising (a) at least one acid-labile proton pumpinhibitor, and (b) about 5 to about 30 mEq of antacid wherein theantacid is selected from magnesium hydroxide, magnesium oxide, sodiumcarbonate, sodium bicarbonate, and calcium carbonate, wherein upon oraladministration to a patient: a therapeutically effective amount of theproton pump inhibitor is delivered; and T_(max) of the proton pumpinhibitor is obtained within about 75 minutes. In other embodiments,T_(max) of the proton pump inhibitor is obtained within about 60minutes, or within about 45 minutes, or within about 30 minutes afteradministration.

Also provided herein are pharmaceutical compositions in solid oraldosage forms wherein the wt-% of disintegrant is at least as great asthe wt-% of binder. In some embodiments, the pharmaceutical formulationis substantially free of a binder. In other embodiments, the solid oraldosage form is a tablet (such as a caplet) and the binder is present inan amount of less than about 20 wt %, or less than about 10 wt-%, orless than about 5 wt-%. In other embodiments, the solid oral dosage formis a capsule and the binder is present in an amount of about 0 wt-% toabout 5 wt-%.

The present invention provides a pharmaceutical composition comprising aproton pump inhibiting agent and about 5 mEq to about 11 mEq of antacidfor oral administration and ingestion by a subject.

Pharmaceutical formulations are included that comprise (a) at least oneacid-labile proton pump inhibitor, and (b) between about 5 mEq to about11 mEq of antacid, wherein upon oral administration to a subject, theoral bioavailability of the proton pump inhibitor is at least 25% andthe maximum serum concentration of the proton pump inhibitor is obtainedwithin about 75 minutes after administration. In other embodiments, themaximum serum concentration is obtained within about 60 minutes, orwithin about 50 minutes, or within about 40 minutes, or within about 30minutes, or within about 20 minutes after administration of thepharmaceutical formulation. In still other embodiments, the oralbioavailability of the proton pump inhibitor is about 25% to about 60%,or about 30% to about 50%, or at least about 30%, or at least about 35%,or at least about 40%.

Pharmaceutical formulations that comprise (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid, wherein the pharmaceutical formulation is bioequivalent to apharmaceutical formulation comprising (a) at least one acid-labileproton pump inhibitor, and (b) greater than 11 mEq of antacid. In someembodiments, the area under the serum concentration time curve for theproton pump inhibitor is within about ±15% of the area under the serumconcentration time curve for the proton pump inhibitor when anadministered with greater than 11 mEq of antacid. In other embodiments,the area under the serum concentration time curve for the proton pumpinhibitor is within about ±10% of the area under the serum concentrationtime curve for the proton pump inhibitor when an administered withgreater than 11 mEq of antacid. In still other embodiments, the areaunder the serum concentration time curve for the proton pump inhibitoris within about ±5% of the area under the serum concentration time curvefor the proton pump inhibitor when administered with greater than 11 mEqof antacid.

Pharmaceutical formulations that comprise (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid, wherein the pharmaceutical formulation is bioequivalent to apharmaceutical formulation comprising (a) at least one acid-labileproton pump inhibitor, and (b) greater than 15 mEq of antacid. In someembodiments, the area under the serum concentration time curve for theproton pump inhibitor is within about ±15%, or within about ±10%, orwithin about ±5% of the area under the serum concentration time curvefor the proton pump inhibitor when an administered with greater than 15mEq of antacid.

Pharmaceutical formulations that comprise (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid, wherein the pharmaceutical formulation is bioequivalent to apharmaceutical formulation comprising (a) at least one acid-labileproton pump inhibitor, and (b) greater than 20 mEq of antacid. In someembodiments, the area under the serum concentration time curve for theproton pump inhibitor is within about ±15%, or within about ±10%, orwithin about ±5% of the area under the serum concentration time curvefor the proton pump inhibitor when an administered with greater than 20mEq of antacid.

Pharmaceutical formulations comprising (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid wherein the pharmaceutical formulation is bioequivalent to aproton pump inhibitor product. In some embodiments, the pharmaceuticalformulation is bioequivalent to Priolosec®, Nexium®, Prevacid®,Protonic®, and Aciphex®. In other embodiments, the maximum concentrationof the proton pump inhibitor for the pharmaceutical formulation iswithin about 80% and about 120% of the maximum concentration (Cmax) forthe proton pump inhibitor product. In some embodiments, the maximumconcentration of the proton pump inhibitor for the pharmaceuticalformulation is within about 80% and about 120% of the maximumconcentration (Cmax) for the proton pump inhibitor product when thepharmaceutical formulation and proton pump inhibitor product areadministered to the same patient.

Pharmaceutical formulations comprising (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid are provided herein, wherein upon oral administration to asubject, the pharmaceutical composition has an area under the serumconcentration time curve (AUC) for the proton pump inhibitor that isequivalent to an area under the serum concentration time curve (AUC) forthe proton pump inhibitor when an enteric form of the proton pumpinhibitor is delivered without antacid. In some embodiments, the areaunder the serum concentration time curve for the proton pump inhibitoris within about ±20% of the area under the serum concentration timecurve for the proton pump inhibitor when an enteric form of the protonpump inhibitor is delivered without antacid. In still other embodiments,the area under the serum concentration time curve for the proton pumpinhibitor is within about ±15%, or within about ±10%, or with about ±5%of the area under the serum concentration time curve for the proton pumpinhibitor when an enteric form of the proton pump inhibitor is deliveredwithout antacid.

Pharmaceutical formulations comprising (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid are provided herein, wherein a therapeutic dose of the protonpump inhibitor is delivered as a single capsule, tablet, or caplet.

A pharmaceutical formulations comprising (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid, wherein upon oral administration to a patient: atherapeutically effective amount of the proton pump inhibitor isdelivered; the antacid increases the gastric pH to at least about 3.5for no more than about 30 minutes measured by a simulated stomach modelsuch as Fuchs kinetic in-vitro pH model; and the maximum concentrationof the proton pump inhibitor is obtained within about 75 minutes arealso provided herein. In some embodiments, the antacid increases thegastric pH to at least about 3.5 for less than about 30 minutes, or lessthan about 25 minutes, or less than about 20 minutes, or less than about15 minutes, or less than about 10 minutes. In other embodiments, themaximum concentration of the proton pump inhibitor is obtained withinabout 60 minutes.

Pharmaceutical formulations comprising (a) at least one acid-labileproton pump inhibitor, and (b) between about 5 mEq to about 11 mEq ofantacid are provided herein, wherein the formulation comprises about 5mgs to about 200 mgs of the proton pump inhibitor. In other embodiments,the pharmaceutical formulation comprises about 10 mgs, or about 20 mgs,or about 30 mgs, or about 40 mgs, or about 50 mgs, or about 60 mgs, orabout 80 mgs, or about 120 mgs of the proton pump inhibitor. In yetother embodiments, the pharmaceutical formulation comprises about 5 mEq,or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about10 mEq, or about 11 mEq of antacid.

Compositions are provided such that an initial serum concentration ofthe proton pump inhibitor is greater than about 100 ng/ml at any timewithin about 30 minutes after administering the formulation. Initialserum concentration of the proton pump inhibitor can be greater thanabout 100 ng/ml at any time within about 15 minutes. Initial serumconcentration of the proton pump inhibitor can be greater than about 200ng/ml at any time within about 1 hour after administration, greater thanabout 300 ng/ml at any time within about 45 minutes afteradministration.

Compositions are provided such that a serum concentration of greaterthan about 100 ng/ml can be maintained from at least about 30 minutes toabout 1 hour after administration of the composition. Compositions areprovided such that a serum concentration of proton pump inhibitorgreater than about 100 ng/ml can be maintained from at least about 15minutes to about 30 minutes after administration. Compositions areprovided such that a serum concentration of greater than about 100 ng/mlcan be maintained from at least about 30 minutes to about 45 minutesafter administration. Compositions are provided such that a serumconcentration of greater than about 250 ng/ml can be maintained from atleast about 30 minutes to about 1 hour after administration.Compositions are provided such that a serum concentration of greaterthan about 250 ng/ml can be maintained from at least about 30 minutes toabout 45 minutes after administration. Compositions are provided suchthat a serum concentration of greater than about 250 ng/ml can bemaintained from at least about 15 minutes to about 30 minutes afteradministration.

Compositions of the invention can be administered in an amount tomaintain a serum concentration of the proton pump inhibitor greater thanabout 150 ng/ml from about 15 minutes to about 1 hour afteradministration. Compositions of the invention can be administered in anamount to maintain a serum concentration of the proton pump inhibitorgreater than about 150 ng/ml from about 15 minutes to about 1.5 hoursafter administration. Compositions of the invention can be administeredin an amount to maintain a serum concentration of the proton pumpinhibitor greater than about 100 ng/ml from about 15 minutes to about1.5 hours after administration. Compositions of the invention can beadministered in an amount to maintain a serum concentration of theproton pump inhibitor greater than about 150 ng/ml from about 15 minutesto about 30 minutes after administration.

Compositions of the invention can be administered in an amount toachieve an initial serum concentration of the proton pump inhibitorgreater than about 150 ng/ml at any time from about 5 minutes to about30 minutes after administration. Compositions of the invention can beadministered in an amount to achieve an initial serum concentration ofthe proton pump inhibitor greater than about 150 ng/ml at any timewithin about 30 minutes after administration.

Compositions are provided wherein, upon oral administration to thesubject, the composition provides a pharmacokinetic profile such that atleast about 50% of total area under serum concentration time curve (AUC)for the proton pump inhibitor occurs within about 2 hours afteradministration of a single dose of the composition to the subject.Compositions are provided wherein, upon oral administration to thesubject, the area under the serum concentration time curve (AUC) for theproton pump inhibitor in the first 2 hours is at least about 60% of thetotal area. Compositions are provided wherein the area under the serumconcentration time curve (AUC) for the proton pump inhibitor in thefirst 2 hours is at least about 70% of the total area.

Compositions are provided wherein at least about 50% of total area underthe serum concentration time curve (AUC) for the proton pump inhibitoroccurs within about 1.75 hours after administration of a single dose ofthe composition to the subject. Compositions are provided wherein atleast about 50% of total area under the serum concentration time curve(AUC) for the proton pump inhibitor occurs within about 1.5 hours afteradministration of a single dose of the composition to the subject.Compositions are provided wherein at least about 50% of total area underthe serum concentration time curve (AUC) for the proton pump inhibitoroccurs within about 1 hour after administration of a single dose of thecomposition to the subject.

Compositions and methods are provided wherein, upon oral administrationto the subject, the composition provides a pharmacokinetic profile suchthat the proton pump inhibitor reaches a maximum serum concentrationwithin about 75 minutes after administration of a single dose of thepharmaceutical formulation. In yet other embodiments the maximum serumconcentration is reached within about 60 minutes after administration,or within about 45 minutes after administration of the pharmaceuticalformulation. In still other embodiments, the maximum serum concentrationis reached within about 30 minutes after administration of thepharmaceutical formulation.

Methods are provided for treating a gastric acid related disorderincluding, but not limited to duodenal ulcer disease, gastric ulcerdisease, gastroesophageal reflux disease, erosive esophagitis, poorlyresponsive symptomatic gastroesophageal reflux disease, pathologicalgastrointestinal hypersecretory disease, Zollinger Ellison syndrome,heartburn, esophageal disorder, and acid dyspepsia. Method are providedwherein the proton pump inhibitor treats an episode of gastric acidrelated disorder.

In some embodiments, the proton pump inhibitor is a substituted bicyclicaryl-imidazole. In other embodiments, the proton pump inhibitor isselected from the group consisting of omeprazole, hydroxyomeprazole,esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole,dontoprazole, habeprazole, perprazole, ransoprazole, pariprazole,leminoprazole; or a free base, free acid, salt, hydrate, ester, amide,enantiomer, isomer, tautomer, polymorph, or prodrug thereof. In stillother embodiments, the proton pump inhibitor is selected fromlansoprazole, tenatoprazole, esomeprazole, rabeprazole and pantoprazole,or a free base, free acid, salt, hydrate, ester, amide, enantiomer,isomer, tautomer, polymorph, or prodrug thereof.

Pharmaceutical formulations of the present invention comprise, forexample, about 5 mgs to about 200 mgs of a proton pump inhibitor. Invarious embodiments, the pharmaceutical formulation may comprise about10 mgs, or about 15 mgs, or about 20 mgs, or about 40 mgs, or about 60mgs, or about 120 mgs of the proton pump inhibitor.

In various embodiments of the present invention, the antacid is analkaline metal salt or a Group IA metal selected from a bicarbonate saltof a Group IA metal, a carbonate salt of a Group IA metal. In otherembodiments, the antacid can be, but is not limited to, an amino acid,an alkali metal salt of an amino acid, aluminum hydroxide, aluminumhydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminummagnesium hydroxide, aluminum hydroxide/magnesium hydroxideco-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate,aluminum glycinate, calcium acetate, calcium bicarbonate, calciumborate, calcium carbonate, calcium citrate, calcium gluconate, calciumglycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate,calcium phosphate, calcium succinate, calcium tartrate, dibasic sodiumphosphate, dipotassium hydrogen phosphate, dipotassium phosphate,disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxidegel, L-arginine, magnesium acetate, magnesium aluminate, magnesiumborate, magnesium bicarbonate, magnesium carbonate, magnesium citrate,magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesiummetasilicate aluminate, magnesium oxide, magnesium phthalate, magnesiumphosphate, magnesium silicate, magnesium succinate, magnesium tartrate,potassium acetate, potassium carbonate, potassium bicarbonate, potassiumborate, potassium citrate, potassium metaphosphate, potassium phthalate,potassium phosphate, potassium polyphosphate, potassium pyrophosphate,potassium succinate, potassium tartrate, sodium acetate, sodiumbicarbonate, sodium borate, sodium carbonate, sodium citrate, sodiumgluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate,sodium phthalate, sodium phosphate, sodium polyphosphate, sodiumpyrophosphate, sodium sesquicarbonate, sodium succinate, sodiumtartrate, sodium tripolyphosphate, synthetic hydrotalcite,tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassiumphosphate, trisodium phosphate, trometamol, Effersoda® (a mixture ofsodium bicarbonate and sodium carbonate) and mixtures thereof. In yetother embodiments, the antacid can be sodium bicarbonate, sodiumcarbonate, Effersoda®, calcium carbonate, magnesium oxide, magnesiumhydroxide, magnesium carbonate, aluminum hydroxide, and mixturesthereof. In some embodiments, the composition is substantially free ofsucralfate. In other embodiments, the composition does not contain anamino acid buffer. In still other embodiments, the composition is acombination of two or more antacids, wherein at least two of theantacids are not amino acids.

Pharmaceutical formulations of the present invention may comprisevarying amounts of antacid. For example, in some embodiments, thepharmaceutical formulation comprises about 100 to 3000 mg of antacid. Inother embodiments, the pharmaceutical formulation comprises about 400 toabout 1300 mg of antacid. In still other embodiments the pharmaceuticalformulation comprises about 5 mEq to about 30 mEq, or about 8 mEq toabout 20 mEq, or about 10 mEq to about 15 mEq of antacid. In furtherembodiments, the pharmaceutical formulations comprise about 13 mEq ofantacid.

Pharmaceutical formulations of the present invention may be in the formof a tablet, (including a suspension tablet, a chewable tablet, afast-melt tablet, a bite-disintegration tablet, a rapid-disintegrationtablet, an effervescent tablet, or a caplet), a pill, a powder(including a sterile packaged powder, a dispensable powder, or aneffervescent powder) a capsule (including both soft or hard capsules,e.g., capsules made from animal-derived gelatin or plant-derived HPMC) alozenge, a sachet, a troche, pellets, granules, or an aerosol. In someembodiments, the pharmaceutical formulation is in the form of a powderfor suspension. In other embodiments, the pharmaceutical formulation isin the form of a tablet, including but not limited to, a chewabletablet. Additionally, pharmaceutical formulations of the presentinvention may be administered as a single capsule or in multiple capsuledosage form. In some embodiments, the pharmaceutical formulation isadministered in two, or three, or four, capsules.

In various embodiments of the present invention, the proton pumpinhibitor may be microencapsulated with a material that enhances theshelf life of the pharmaceutical formulation. In some embodiments, thematerial that enhances the shelf life of the pharmaceutical formulationis selected from the group consisting of cellulose hydroxypropyl ethers;low-substituted hydroxypropyl ethers; cellulose hydroxypropyl methylethers; methylcellulose polymers; ethylcelluloses and mixtures thereof;polyvinyl alcohol; hydroxyethylcelluloses; carboxymethylcelluloses andsalts of carboxymethylcelluloses; polyvinyl alcohol and polyethyleneglycol co-polymers; monoglycerides; triglycerides; polyethylene glycols,modified food starch, acrylic polymers; mixtures of acrylic polymerswith cellulose ethers; cellulose acetate phthalate; sepifilms,cyclodextrins; and mixtures thereof. In other embodiments, the materialthat enhances the shelf life of the pharmaceutical formulation furthercomprise an antioxidant, sodium bicarbonate, or a plasticizer.

In various embodiments, the pharmaceutical formulations of the presentinvention further comprise or more excipients selected from the groupconsisting of parietal cell activators, organic solvents, erosionfacilitators, flavoring agents, sweetening agents, diffusionfacilitators, antioxidants and carrier materials selected from binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents,anti-adherents, and antifoaming agents.

DESCRIPTION OF THE FIGURES

FIG. 1 shows a comparison of buffer systems comprising various mixturesof NaHCO₃ and Mg(OH)₂.

FIG. 2 shows a comparison of buffer systems comprising various mixturesof NaHCO₃ and Mg(OH)₂.

FIG. 3 shows the particle size effect of magnesium hydroxide onin-vitro/in-vivo neutralization for immediate release capsuleformulations SAN-10A, SAN-10B and SAN-10D.

FIG. 4 shows the particle size effect of magnesium hydroxide on thepharmacokinetics of various formulations.

FIG. 5 shows the binder effect on various pharmaceutical formulations.

FIG. 6 shows the capsule dissolution effect with 5% binder as comparedto a powder for suspension.

FIG. 7 shows the pH study results of high/low Ac-Di-Sol (disintegrant).

FIG. 8 shows the pharmacokinetic study results of high/low Ac-Di-Sol(disintegrant) as compared to Prilosec.

FIG. 9 shows the pharmacokinetic profiles for six differentpharmaceutical formulations.

FIG. 10 is a summary of exemplary formulations with the ANC present inthe individual pharmaceutical formulations.

FIG. 11 is a summary of the pharmacokinetics of various formulations.

FIG. 12 shows the capsule stability of SAN-10E, SAN-10BB, and SAN-10B.

FIG. 13 compares the concentration/time curve for Prilosec® to theconcentration/time curve of SAN-10K (10.5 mEq of Sodium Bicarbonate and40 mg omeprazole).

FIG. 14 is a graph comparing the average pharmacokinetic releaseprofiles of immediate release omeprazole chewable tablets (SAN-15A,SAN-15B and SAN-15C), capsules (SAN-10A, SAN-10B, SAN-10C, SAN-10E,SAN-10H, SAN-10BB), and a caplets (SAN-15D and SAN-15E) according to thepresent invention as compared to Priolosec® enteric coated omeprazole 40mg. The compositions according to the present invention are all setforth in Table 13A, below.

FIG. 15 is a graph comparing the average pharmacokinetic releaseprofiles of SAN-10BB (P9), SAN-10H (P8) and SAN-10B (P4) omeprazolecapsules, 40 mg per dose. The formulations are described in detail inExample 13.

FIG. 16 is a graph comparing the Cmax and Tmax values for immediaterelease omeprazole powder, capsule, chew tab and caplet formulationsaccording to the present invention with those of Prilosec® brand entericcoated omeprazole. The omeprazole powder is immediate release omeprazolepowder for suspension, 20 or 40 mg micronized omeprazole and 1680 mg (20mEq) of sodium bicarbonate, described in Example 16; the chewabletablets are 20 or 40 mg SAN-38 chewable tablets, as described herein;the capsules are SAN-7E (40 mg) or SAN-7F (20 mg) capsules as decribedin Examples 7, 14 and 15, below.

FIG. 17 is a graph comparing the average pharmacokinetic releaseprofiles of immediate release omeprazole suspension (20 mg)(Example 16),chewable tablets (20 mg), capsule (20 mg)(Example 7F), and Prilosec®brand enteric coated omeprazole (20) mg from the human clinical trialdescribed in Example 14B, Day 1.

FIG. 18 is a graph comparing the average pharmacokinetic releaseprofiles of immediate release omeprazole suspension (40 mg)(Example 16),chewable tablets (40 mg), capsule (40 mg)(Example 7E), and Prilosec®enteric coated omeprazole (40 mg) from the human clinical trialdescribed in Example 15B, Day 1.

FIG. 19 is a graph comparing the mean peak plasma concentration (Cmax)verses the time at which Cmax is observed (Tmax) for 20 mg and 40 mgimmediate release chewable tablets, capsules (SAN-7F, SAN-7E,respectively), and immediate release omeprazole suspension according tothe present invention and 20 and 40 mg Prilosec® enteric coatedomeprazole. The data are from the human clinical trial in Examples 14Band 15 B, Day 1.

FIG. 20 is a graph comparing the average pharmacokinetic releaseprofiles of immediate release omeprazole suspension (20 mg), chewabletablets (20 mg), capsule (20 mg) (SAN-7F) according to the presentinvention with Prilosec (20 mg) from the human clinical trial in Example14B, Day 7.

FIG. 21 is a graph comparing the average pharmacokinetic releaseprofiles of immediate release omeprazole suspension (40 mg), chewabletablets (40 mg), capsule (40 mg) (SAN-7E) according to the presentinvention with Prilosec® brand enteric coated omeprazole (40 mg) fromthe human clinical trial in Example 15B, Day 7.

FIG. 22 is a graph comparing the mean peak plasma concentration (Cmax)verses the time at which Cmax is observed (Tmax) for immediate releaseomeprazole chewable tablets, capsules, and suspension according to thepresent invention (20 and 40 mg) and Prilosec® brand enteric coatedomeprazole (20 and 40 mg) from the human clinical trial set forth in14B, 15B Day 7.

FIG. 23 is a graph comparing the Cmax versus Tmax of immediate releaseomeprazole chewable tablets, capsules, and suspension according to thepresent invention and Prilosec® brand enteric coated omeprazole. Thedata for both 20 mg and 40 mg doses are from the clinical trial setforth in Examples 14B, 15B, Days 1 and 7.

FIG. 24 is a flow chart depicting Manufacturing Process of immediaterelease capsules according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods, kits, combinations, andcompositions for treating a condition or disorder where treatment withan acid labile proton pump inhibitor is indicated. Also provided aremethods, kits, combinations, and compositions for treating, preventingor reducing the risk of developing a gastrointestinal disorder ordisease, or the symptoms associated with, or related to agastrointestinal disorder or disease in a subject in need thereof.

While the present invention may be embodied in many different forms,several specific embodiments are discussed herein with the understandingthat the present disclosure is to be considered only as anexemplification of the principles of the invention, and it is notintended to limit the invention to the embodiments illustrated. Forexample, where the present invention is illustrated herein withparticular reference to omeprazole, hydroxyomeprazole, esomeprazole,tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole,habeprazole, periprazole, ransoprazole, pariprazole, or leminoprazole,it will be understood that any other proton pump inhibiting agent, ifdesired, can be substituted in whole or in part for such agents in themethods, kits, combinations, and compositions herein described.

To more readily facilitate an understanding of the invention and itspreferred embodiments, the meanings of terms used herein will becomeapparent from the context of this specification in view of common usageof various terms and the explicit definitions of other terms provided inthe glossary below or in the ensuing description.

GLOSSARY

As used herein, the terms “comprising,” “including,” and “such as” areused in their open, non-limiting sense.

The term “about” is used synonymously with the term “approximately.” Asone of ordinary skill in the art would understand, the exact boundary of“about” will depend on the component of the composition. Illustratively,the use of the term “about” indicates that values slightly outside thecited values, i.e., plus or minus 0.1% to 10%, which are also effectiveand safe.

The phrase “acid-labile pharmaceutical agent” refers to anypharmacologically active drug subject to acid catalyzed degradation.

“Anti-adherents,” “glidants,” or “anti-adhesion” agents preventcomponents of the formulation from aggregating or sticking and improveflow characteristics of a material. Such compounds include, e.g.,colloidal silicon dioxide such as Cab-o-Sil®; tribasic calciumphosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate,magnesium stearate, calcium stearate, sodium stearate, kaolin, andmicronized amorphous silicon dioxide (Syloid®) and the like.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

“Bioavailability” refers to the extent to which an active moiety, e.g.,drug, prodrug, or metabolite, is absorbed into the general circulationand becomes available at the site of drug action in the body. Thus, aproton pump inhibitor administered through IV is 100% bioavailable.“Oral bioavailability” refers to the extent to which the proton pumpinhibitor (or other active moiety) is absorbed into the generalcirculation and becomes available at the site of drug action in the bodywhen the pharmaceutical composition is taken orally.

“Bioequivalence” or “bioequivalent” means that the area under the serumconcentration time curve (AUC) and the peak serum concentration(C_(max)) are each within 80% and 120%.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility withthe proton pump inhibitor and the release profile properties of thedesired dosage form. Exemplary carrier materials include, e.g., binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. “Pharmaceutically compatible carrier materials” may comprise,e.g., acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, sodium caseinate, soy lecithin, sodium chloride, tricalciumphosphate, dipotassium phosphate, sodium stearoyl lactylate,carrageenan, monoglyceride, diglyceride, pregelatinized starch, and thelike. See, e.g., Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

“Character notes” include, e.g., aromatics, basis tastes, and feelingfactors. The intensity of the character note can be scaled from 0-none,1-slight, 2-moderate, or 3-strong.

A “derivative” is a compound that is produced from another compound ofsimilar structure by the replacement of substitution of an atom,molecule or group by another suitable atom, molecule or group. Forexample, one or more hydrogen atom of a compound may be substituted byone or more alkyl, acyl, amino, hydroxyl, halo, haloalkyl, aryl,heteroaryl, cycloaolkyl, heterocycloalkyl, or heteroalkyl group toproduce a derivative of that compound.

“Diffusion facilitators” and “dispersing agents” include materials thatcontrol the diffusion of an aqueous fluid through a coating. Exemplarydiffusion facilitators/dispersing agents include, e.g., hydrophilicpolymers, electrolytes, Tween® 60 or 80, PEG and the like. Combinationsof one or more erosion facilitator with one or more diffusionfacilitator can also be used in the present invention.

“Diluents” increase bulk of the composition to facilitate compression.Such compounds include e.g., lactose; starch; mannitol; sorbitol;dextrose; microcrystalline cellulose such as Avicel®; dibasic calciumphosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calciumphosphate; anhydrous lactose; spray-dried lactose; pregelatinzed starch;compressible sugar, such as Di-Pac® (Amstar); mannitol;hydroxypropylmethylcellulose; sucrose-based diluents; confectioner'ssugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate;calcium lactate trihydrate; dextrates; hydrolyzed cereal solids;amylose; powdered cellulose; calcium carbonate; glycine; kaolin;mannitol; sodium chloride; inositol; bentonite; and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.

“Disintegration agents” facilitate the breakup or disintegration of asubstance. Examples of disintegration agents include a starch, e.g., anatural starch such as corn starch or potato starch, a pregelatinizedstarch such as National 1551 or Amijel®, or sodium starch glycolate suchas Promogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

“Drug absorption” or “absorption” refers to the process of movement fromthe site of administration of a drug toward the systemic circulation,e.g., into the bloodstream of a subject.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug once the small intestineis reached. Generally, the enteric coating comprises a polymericmaterial that prevents release in the low pH environment of the stomachbut that ionizes at a slightly higher pH, typically a pH of 4 or 5, andthus dissolves sufficiently in the small intestines to gradually releasethe active agent therein.

The “enteric form of the proton pump inhibitor” is intended to mean thatsome or most of the proton pump inhibitor has been enterically coated toensure that at least some of the drug is released in the proximal regionof the small intestine (duodenum), rather than the acidic environment ofthe stomach.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose; dextrates;dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” or “sweeteners” useful in the pharmaceuticalcompositions of the present invention include, e.g., acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream,tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut,watermelon, wild cherry, wintergreen, xylitol, or any combination ofthese flavoring ingredients, e.g., anise-menthol, cherry-anise,cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon,lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint,and mixtures thereof.

“Gastrointestinal fluid” is the fluid of stomach secretions of a subjector the saliva of a subject after oral administration of a composition ofthe present invention, or the equivalent thereof. An “equivalent ofstomach secretion” includes, e.g., an in vitro fluid having similarcontent and/or pH as stomach secretions such as a 1% sodium dodecylsulfate solution or 0.1N HCl solution in water.

“Half-life” refers to the time required for the plasma drugconcentration or the amount in the body to decrease by 50% from itsmaximum concentration.

“Lubricants” are compounds that prevent, reduce or inhibit adhesion orfriction of materials. Exemplary lubricants include, e.g., stearic acid;calcium hydroxide; talc; sodium stearyl fumerate; a hydrocarbon such asmineral oil, or hydrogenated vegetable oil such as hydrogenated soybeanoil (Sterotex®); higher fatty acids and their alkali-metal and alkalineearth metal salts, such as aluminum, calcium, magnesium, zinc, stearicacid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid,sodium benzoate, sodium acetate, sodium chloride, leucine, apolyethylene glycol or a methoxypolyethylene glycol such as Carbowax™,sodium oleate, glyceryl behenate, polyethylene glycol, magnesium orsodium lauryl sulfate, colloidal silica such as Syloid™, Carb-O-Sil®, astarch such as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of bloodserum, of a therapeutic agent that is absorbed into the bloodstreamafter administration. One of ordinary skill in the art would be able tomeasure the serum concentration or plasma concentration of a proton pumpinhibitor or a prokinetic agent. See, e.g., Gonzalez H. et al., J.Chromatogr. B. Analyt. Technol. Biomed. Life Sci., vol. 780, pp 459-65,(Nov. 25, 2002).

“Parietal cell activators” or “activators” stimulate the parietal cellsand enhance the pharmaceutical activity of the proton pump inhibitor.Parietal cell activators include, e.g., chocolate; alkaline substancessuch as sodium bicarbonate; calcium such as calcium carbonate, calciumgluconate, calcium hydroxide, calcium acetate and calciumglycerophosphate; peppermint oil; spearmint oil; coffee; tea and colas(even if decaffeinated); caffeine; theophylline; theobromine; aminoacids (particularly aromatic amino acids such as phenylalanine andtryptophan); and combinations thereof.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction.

“Pharmacokinetics” refers to the factors which determine the attainmentand maintenance of the appropriate concentration of drug at a site ofaction.

“Plasma concentration” refers to the concentration of a substance inblood plasma or blood serum of a subject. It is understood that theplasma concentration of a therapeutic agent may vary many-fold betweensubjects, due to variability with respect to metabolism of therapeuticagents. In accordance with one aspect of the present invention, theplasma concentration of a proton pump inhibitors and/or prokinetic agentmay vary from subject to subject. Likewise, values such as maximumplasma concentration (C_(max)) or time to reach maximum serumconcentration (T_(max)), or area under the serum concentration timecurve (AUC) may vary from subject to subject. Due to this variability,the amount necessary to constitute “a therapeutically effective amount”of proton pump inhibitor, prokinetic agent, or other therapeutic agent,may vary from subject to subject. It is understood that when mean plasmaconcentrations are disclosed for a population of subjects, these meanvalues may include substantial variation.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, and triacetin.

“Prevent” or “prevention” when used in the context of a gastric acidrelated disorder means no gastrointestinal disorder or diseasedevelopment if none had occurred, or no further gastrointestinaldisorder or disease development if there had already been development ofthe gastrointestinal disorder or disease. Also considered is the abilityof one to prevent some or all of the symptoms associated with thegastrointestinal disorder or disease.

A “prodrug” refers to a drug or compound in which the pharmacologicalaction results from conversion by metabolic processes within the body.Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrugwhich renders it less active and/or confers solubility or some otherproperty to the drug. Once the chemical group has been cleaved and/ormodified from the prodrug the active drug is generated. Prodrugs may bedesigned as reversible drug derivatives, for use as modifiers to enhancedrug transport to site-specific tissues. The design of prodrugs to datehas been to increase the effective water solubility of the therapeuticcompound for targeting to regions where water is the principal solvent.See, e.g., Fedorak et al., Am. J. Physiology, 269:G210-218 (1995);McLoed et al., Gastroenterol., 106:405-413 (1994); Hochhaus et al.,Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J.Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics,47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriersin Drug Design, American Pharmaceutical Association and Pergamon Press,1987.

“Proton pump inhibitor product” refers to a product sold on the market.Proton pump inhibitor products include, for example, Priolosec®,Nexium®, Prevacid®, Protonic®, and Aciphex®.

“Serum concentration” refers to the concentration of a substance such asa therapeutic agent, in blood plasma or blood serum of a subject. It isunderstood that the serum concentration of a therapeutic agent may varymany-fold between subjects, due to variability with respect tometabolism of therapeutic agents. In accordance with one aspect of thepresent invention, the serum concentration of a proton pump inhibitorsand/or prokinetic agent may vary from subject to subject. Likewise,values such as maximum serum concentration (C_(max)) or time to reachmaximum serum concentration (T_(max)), or total area under the serumconcentration time curve (AUC) may vary from subject to subject. Due tothis variability, the amount necessary to constitute “a therapeuticallyeffective amount” of proton pump inhibitor, prokinetic agent, or othertherapeutic agent, may vary from subject to subject. It is understoodthat when mean serum concentrations are disclosed for a population ofsubjects, these mean values may include substantial variation.

“Solubilizers” include compounds such as citric acid, succinic acid,fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid,sodium bicarbonate, sodium carbonate and the like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, and the like.

“Suspending agents” or “thickening agents” include compounds such aspolyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, orpolyvinylpyrrolidone K30; polyethylene glycol, e.g., the polyethyleneglycol can have a molecular weight of about 300 to about 6000, or about3350 to about 4000, or about 7000 to about 5400; sodiumcarboxymethylcellulose; methylcellulose; hydroxy-propylmethylcellulose;polysorbate-80; hydroxyethylcellulose; sodium alginate; gums, such as,e.g., gum tragacanth and gum acacia; guar gum; xanthans, includingxanthan gum; sugars; cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose; polysorbate-80;sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylatedsorbitan monolaurate; povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF); and the like.

A “therapeutically effective amount” or “effective amount” is thatamount of a pharmaceutical agent to achieve a pharmacological effect.The term “therapeutically effective amount” includes, for example, aprophylactically effective amount. An “effective amount” of a protonpump inhibitor is an amount effective to achieve a desired pharmacologiceffect or therapeutic improvement without undue adverse side effects.For example, an effective amount of a proton pump inhibitor refers to anamount of proton pump inhibitor that reduces acid secretion, or raisesgastrointestinal fluid pH, or reduces gastrointestinal bleeding, orreduces the need for blood transfusion, or improves survival rate, orprovides for a more rapid recovery from a gastric acid related disorder.The effective amount of a pharmaceutical agent will be selected by thoseskilled in the art depending on the particular patient and the diseaselevel. It is understood that “an effect amount” or “a therapeuticallyeffective amount” can vary from subject to subject, due to variation inmetabolism of therapeutic agents such as proton pump inhibitors and/orprokinetic agents, age, weight, general condition of the subject, thecondition being treated, the severity of the condition being treated,and the judgment of the prescribing physician.

“Total intensity of aroma” is the overall immediate impression of thestrength of the aroma and includes both aromatics and nose feelsensations.

“Total intensity of flavor” is the overall immediate impression of thestrength of the flavor including aromatics, basic tastes and mouth feelsensations.

“Treat” or “treatment” as used in the context of a gastric acid relateddisorder refers to any treatment of a disorder or disease associatedwith a gastrointestinal disorder, such as preventing the disorder ordisease from occurring in a subject which may be predisposed to thedisorder or disease, but has not yet been diagnosed as having thedisorder or disease; inhibiting the disorder or disease, e.g., arrestingthe development of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder. Thus, as used herein, the term “treat” is usedsynonymously with the term “prevent.”

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium oleate, sodium lauryl sulfate, and the like.

Proton Pump Inhibitors

The terms “proton pump inhibitor,” “PPI,” and “proton pump inhibitingagent” can be used interchangeably to describe any acid labilepharmaceutical agent possessing pharmacological activity as an inhibitorof H+/K+-ATPase. A proton pump inhibitor may, if desired, be in the formof free base, free acid, salt, ester, hydrate, anhydrate, amide,enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or thelike, provided that the free base, salt, ester, hydrate, amide,enantiomer, isomer, tautomer, prodrug, or any other pharmacologicallysuitable derivative is therapeutically active.

In various embodiments, the proton pump inhibitor can be a substitutedbicyclic aryl-imidazole, wherein the aryl group can be, e.g., apyridine, a phenyl, or a pyrimidine group and is attached to the 4- and5-positions of the imidazole ring. Proton pump inhibitors comprising asubstituted bicyclic aryl-imidazoles include, but are not limited to,omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole,rabeprazole, dontoprazole, habeprazole, perprazole, tenatoprazole,ransoprazole, pariprazole, leminoprazole, or a free base, free acid,salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph,prodrug, or derivative thereof. See, e.g., The Merck Index, Merck & Co.Rahway, N.J. (2001).

Other proton pump inhibitors include but are not limited to: soraprazan(Altana); ilaprazole (U.S. Pat. No. 5,703,097) (Il-Yang); AZD-0865(AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB-641257)(2-pyrimidinamine,4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-monohydrochloride)(YuHan);BY-112 (Altana); SPI-447(Imidazo(1,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3-thienyl)(Shinnippon);3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imidazo(1,2-a)pyridine(PCT Publication WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950(3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imidazo(1,2-a)pyridine)(AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP 700899)(Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959)(AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335)(Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574(Altana); Pharmaprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck);AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis);WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana);YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854)(Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax);FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca);nepaprazole (Toa Eiyo); HN-11203 (Nycomed Pharma); OPC-22575;pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SKandF-95601(GSK, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer);S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); SKandF-96067 (EP259174) (Altana); SUN 8176 (Daiichi Phama); Ro-18-5362 (Roche);ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or a freebase, free acid, salt, hydrate, ester, amide, enantiomer, isomer,tautomer, polymorph, prodrug, or derivative of these compounds.

Still other proton pump inhibitors contemplated by the present inventioninclude those described in the following U.S. Pat. Nos. 4,628,098;4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560;5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478;5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914;5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875;6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974;5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281;6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167.

Other substituted bicyclic aryl-imidazole compounds as well as theirsalts, hydrates, esters, amides, enantiomers, isomers, tautomers,polymorphs, prodrugs, and derivatives may be prepared using standardprocedures known to those skilled in the art of synthetic organicchemistry. See, e.g., March, Advanced Organic Chemistry: Reactions,Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992);Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth etal., Core Organic Chemistry (1998); and Weisermel et al., IndustrialOrganic Chemistry (2002).

“Pharmaceutically acceptable salts,” or “salts,” include, e.g., the saltof a proton pump inhibitor prepared from formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric,galactaric and galacturonic acids.

In one embodiment, acid addition salts are prepared from the free baseusing conventional methodology involving reaction of the free base witha suitable acid. Suitable acids for preparing acid addition saltsinclude both organic acids, e.g., acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like.

In other embodiments, an acid addition salt is reconverted to the freebase by treatment with a suitable base. In a further embodiment, theacid addition salts of the proton pump inhibitors are halide salts,which are prepared using hydrochloric or hydrobromic acids. In stillother embodiments, the basic salts are alkali metal salts, e.g., sodiumsalt.

Salt forms of proton pump inhibiting agents include, but are not limitedto: a sodium salt form such as esomeprazole sodium, omeprazole sodium,rabeprazole sodium, pantoprazole sodium; or a magnesium salt form suchas esomeprazole magnesium or omeprazole magnesium, described in U.S.Pat. No. 5,900,424; a calcium salt form; or a potassium salt form suchas the potassium salt of esomeprazole, described in U.S. PatentApplication No. 02/0198239 and U.S. Pat. No. 6,511,996. Other salts ofesomeprazole are described in U.S. Pat. No. 4,738,974 and U.S. Pat. No.6,369,085. Salt forms of pantoprazole and lansoprazole are discussed inU.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.

In one embodiment, preparation of esters involves fictionalization ofhydroxyl and/or carboxyl groups which may be present within themolecular structure of the drug. In one embodiment, the esters areacyl-substituted derivatives of free alcohol groups, e.g., moietiesderived from carboxylic acids of the formula RCOOR₁ where R₁ is a loweralkyl group. Esters can be reconverted to the free acids, if desired, byusing conventional procedures such as hydrogenolysis or hydrolysis.

“Amides” may be prepared using techniques known to those skilled in theart or described in the pertinent literature. For example, amides may beprepared from esters, using suitable amine reactants, or they may beprepared from an anhydride or an acid chloride by reaction with an aminegroup such, as ammonia or a lower alkyl amine.

“Tautomers” of substituted bicyclic aryl-imidazoles include, e.g.,tautomers of omeprazole such as those described in U.S. Pat. Nos.6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384;6,369,087; and 6,444,689; and U.S. Patent Publication No. 02/0156103.

An exemplary “isomer” of a substituted bicyclic aryl-imidazole is theisomer of omeprazole including but not limited to isomers described in:Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No.6,150,380; U.S. Patent Publication No. 02/0156284; and PCT PublicationNo. WO 02/085889.

Exemplary “polymorphs” include, but are not limited to, those describedin PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563;4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579;4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743;5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959;5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478;5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708;5,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 6,147,103;6,150,380; 6,166,213; 6,191,148; 5,187,340; 6,268,385; 6,262,086;6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085;6,369,087; 6,380,234; 6,428,810; 6,444,689; and 6,462,0577.

Micronized Proton Pump Inhibitor

Particle size of the proton pump inhibitor can affect the solid dosageform in numerous ways. Since decreased particle size increases insurface area (S), the particle size reduction provides an increase inthe rate of dissolution (dM/dt) as expressed in the Noyes-Whitneyequation below:dM/dt=dS/h(Cs−C)M=mass of drug dissolved; t=time; D=diffusion coefficient of drug;S=effective surface area of drug particles; H=stationary layerthickness; Cs=concentration of solution at saturation; andC=concentration of solution at time t.

Because omeprazole, as well as other proton pump inhibitors, has poorwater solubility, to aid the rapid absorption of the drug product,various embodiments of the present invention use micronized proton pumpinhibitor is used in the drug product formulation.

In various embodiments of the present invention, the proton pumpinhibitor is micronized. In some embodiments, the average particle sizeof at least about 90% the micronized proton pump inhibitor is less thanabout 40 μm, or less than about 35 μm, or less than about 30 μm, or lessthan about 25 μm, or less than about 20 μm, or less than about 15 μm, orless than about 10 μm. In other embodiments, at least 80% of themicronized proton pump inhibitor has an average particle size of lessthan about 40 μm, or less than about 35 μm, or less than about 30 μm, orless than about 25 μm, or less than about 20 μm, or less than about 15μm, or less than about 10 μm. In still other embodiments, at least 70%of the micronized proton pump inhibitor has an average particle size ofless than about 40 μm, or less than about 35 μm, or less than about 30μm, or less than about 25 μm, or less than about 20 μm, or less thanabout 15 μm, or less than about 10 μm.

Compositions are provided wherein the micronized proton pump inhibitoris of a size which allows greater than 75% of the proton pump inhibitorto be released within about 1 hour, or within about 50 minutes, orwithin about 40 minutes, or within about 30 minutes, or within about 20minutes, or within about 10 minutes, or within about 5 minutes ofdissolution testing. In another embodiment of the invention, themicronized proton pump inhibitor is of a size which allows greater than90% of the proton pump inhibitor to be released within about 1 hour, orwithin about 50 minutes, or within about 40 minutes, or within about 30minutes, or within about 20 minutes, or within about 10 minutes, orwithin about 5 minutes of dissolution testing. See U.S. patentapplication Ser. No. 10/893,092, filed Jul. 16, 2004, which claimspriority to U.S. Provisional Application No. 60/488,324 filed Jul. 18,2003, both of which are incorporated by reference in their entirety.

Particle Size of Ingredients

The particle size of the proton pump inhibitor, antacid and excipientsis an important factor which can effect bioavailability, blenduniformity, segregation, and flow properties. In general, smallerparticle sizes of a drug increases the bioabsorption rate of the drugwith substantially poor water solubility by increasing the surface area.The particle size of the drug and excipients can also affect thesuspension properties of the pharmaceutical formulation. For example,smaller particles are less likely to settle and therefore form bettersuspensions.

In various embodiments, the average particle size of the dry powder(which can be administered directly, as a powder for suspension, or usedin a solid dosage form) is less than about 500 microns in diameter, orless than about 450 microns in diameter, or less than about 400 micronsin diameter, or less than about 350 microns in diameter, or less thanabout 300 microns in diameter, or less than about 250 microns indiameter, or less than about 200 microns in diameter, or less than about150 microns in diameter, or less than about 100 microns in diameter, orless than about 75 microns in diameter, or less than about 50 microns indiameter, or less than about 25 microns in diameter, or less than about15 microns in diameter. In other embodiments, the average particle sizeof the aggregates is between about 25 microns in diameter to about 300microns in diameter. In still other embodiments, the average particlesize of the aggregates is between about 25 microns in diameter to about150 microns in diameter. And, in still further embodiments, the averageparticle size of the aggregates is between about 25 microns in diameterto about 100 microns in diameter. The term “average particle size” isintended to describe the average diameter of the particles and/oragglomerates used in the pharmaceutical formulation.

In another embodiment, the average particle size of the insolubleexcipients is between about 5 μm to about 500 μm, or less than about 400μm, or less than about 300 μm, or less than about 200 μm, or less thanabout 150 μm, or less than about 100 μm, or less than about 90 μm, orless than about 80 μm, or less than about 70 μm, or less than about 60μm, or less than about 50 μm, or less than about 40 μm, or less thanabout 30 μm, or less than about 25 μm, or less than about 20 μm, or lessthan about 15 μm, or less than about 10 μm, or less than about 5 μm.

In other embodiments of the present invention, at least about 80% of theparticles have a particle size of less than about 300 μm, or less thanabout 250 μm, or less than about 200 μm, or less than about 150 μm, orless than about 100 μm, or less than about 500 μm. In anotherembodiment, at least about 85% of the dry powder particles have aparticle size of less than about 300 μm, or less than about 250 μm, orless than about 200 μm, or less than about 150 μm, or less than about100 μm, or less than about 50 μm. In still other embodiments of thepresent invention, at least about 90% of the dry powder particles have aparticle size of less than about 300 μm, or less than about 250 μm, orless than about 200 μm, or less than about 150 μm, or less than about100 μm, or less than about 50 μm. In yet another embodiment, at leastabout 95% of the dry powder particles have a particle size of less thanabout 300 μm, or less than about 250 μm, or less than about 200 μm, orless than about 150 μm, or less than about 100 μm, or less than about 50μm.

In other embodiments, the average particle size of the insolublematerial is between about 5 μm to about 250 μm in diameter. In otherembodiments, the average particle size of the insoluble excipients isbetween about 5 μm to about 100 μm, or between about 5 μm to about 80μm, or between about 5 μm to about 50 μm in diameter.

In another embodiment, the particle size of other excipients is chosento be about the same as the particle size of the antacid. In yet anotherembodiment, the particle size of the insoluable excipients is chosen tobe about the same as the particle size of the proton pump inhibitor.

Several factors can be considered in choosing both the proper excipientand its quantity. For example, the excipient should be pharmaceuticallyacceptable. Also, in some examples, rapid dissolution and neutralizationof gastric acid to maintain the gastric pH at about 6.5 for at least onehour. The excipients which will be in contact with the proton pumpinhibitor, if any, should also be chemically compatible with the protonpump inhibitor. “Chemically compatible” is intended to mean that thematerial does not lead to more than 10% degradation of the proton pumpinhibitor when stored at room temperature for at least about 1 year.

Parietal cell activators are administered in an amount sufficient toproduce the desired stimulatory effect without causing untoward sideeffects to patients. In one embodiment, the parietal cell activator isadministered in an amount of about 5 mg to about 2.5 grams per 20 mgdose of the proton pump inhibitor.

Antacids

The pharmaceutical composition of the invention comprises one or moreantacids. A class of antacids useful in the present invention include,but are not limited to, antacids possessing pharmacological activity asa base. In one embodiment, the antacid, when formulated or deliveredwith an proton pump inhibiting agent, functions to substantially preventor inhibit the acid degradation of the proton pump inhibitor bygastrointestinal fluid for a period of time, e.g., for a period of timesufficient to preserve the bioavailability of the proton pump inhibitoradministered. The antacid can be delivered before, during and/or afterdelivery of the proton pump inhibitor. In one aspect of the presentinvention, the antacid includes a salt of a Group IA metal (alkalimetal), including, e.g., a bicarbonate salt of a Group IA metal, acarbonate salt of a Group IA metal; an alkaline earth metal antacid(Group IIA metal); an aluminum antacid; a calcium antacid; or amagnesium antacid.

Other antacids suitable for the present invention include, e.g., alkalimetal (a Group IA metal including, but not limited to, lithium, sodium,potassium, rubidium, cesium, and francium) or alkaline earth metal(Group IIA metal including, but not limited to, beryllium, magnesium,calcium, strontium, barium, radium) carbonates, phosphates,bicarbonates, citrates, borates, acetates, phthalates, tartrate,succinates and the like, such as sodium or potassium phosphate, citrate,borate, acetate, bicarbonate and carbonate.

In various embodiments, an antacid includes an amino acid, an alkalimetal salt of an amino acid, aluminum hydroxide, aluminumhydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminummagnesium hydroxide, aluminum hydroxide/magnesium hydroxideco-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate,aluminum glycinate, calcium acetate, calcium bicarbonate, calciumborate, calcium carbonate, calcium citrate, calcium gluconate, calciumglycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate,calcium phosphate, calcium succinate, calcium tartrate, dibasic sodiumphosphate, dipotassium hydrogen phosphate, dipotassium phosphate,disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxidegel, L-arginine, magnesium acetate, magnesium aluminate, magnesiumborate, magnesium bicarbonate, magnesium carbonate, magnesium citrate,magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesiummetasilicate aluminate, magnesium oxide, magnesium phthalate, magnesiumphosphate, magnesium silicate, magnesium succinate, magnesium tartrate,potassium acetate, potassium carbonate, potassium bicarbonate, potassiumborate, potassium citrate, potassium metaphosphate, potassium phthalate,potassium phosphate, potassium polyphosphate, potassium pyrophosphate,potassium succinate, potassium tartrate, sodium acetate, sodiumbicarbonate, sodium borate, sodium carbonate, sodium citrate, sodiumgluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate,sodium phthalate, sodium phosphate, sodium polyphosphate, sodiumpyrophosphate, sodium sesquicarbonate, sodium succinate, sodiumtartrate, sodium tripolyphosphate, Effersoda® (mixture of sodiumbicarbonate and sodium carbonate), synthetic hydrotalcite,tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassiumphosphate, trisodium phosphate, and trometamol. (See, e.g., listsprovided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Certainproteins or protein hydrolysates that rapidly neutralize acids can serveas antacids in the present invention. Combinations of the abovementioned antacids may also be used in the pharmaceutical compositionsdescribed herein.

The antacids useful in the present invention also include antacids orcombinations of antacids that interact with HCl (or other acids in theenvironment of interest) faster than the proton pump inhibitor interactswith the same acids. When placed in a liquid phase, such as water, theseantacids produce and maintain a pH greater than the pKa of the protonpump inhibitor.

In various embodiments, the antacid is selected from sodium bicarbonate,sodium carbonate, calcium carbonate, magnesium oxide, magnesiumhydroxide, magnesium carbonate, and mixtures thereof.

The antacids useful in the present invention also include antacids orcombinations of antacids that interact with HCl (or other acids in theenvironment of interest) faster than the proton pump inhibitor interactswith the same acids. When placed in a liquid phase, such as water, theseantacids produce and maintain a pH greater than the pKa of the protonpump inhibitor.

In various embodiments, the antacid is selected from sodium bicarbonate,sodium carbonate, calcium carbonate, magnesium oxide, magnesiumhydroxide, magnesium carbonate, aluminum hydroxide, and mixturesthereof. In other embodiments, the antacid is present in thepharmaceutical formulations of the present invention in an amountgreater than about 5 mEq of antacid. In other embodiments, the antacidis present in the pharmaceutical formulations of the present inventionin an amount greater than about 7 mEq of antacid. In other embodiments,the antacid is present in the pharmaceutical formulations of the presentinvention in an amount greater than about 10 mEq of antacid. In otherembodiments, the antacid is present in the pharmaceutical formulationsof the present invention in an amount greater than about 15 mEq ofantacid. In other embodiments, the antacid is present in thepharmaceutical formulations of the present invention in an amountgreater than about 20 mEq of antacid.

In another embodiment, the antacid comprises sodium bicarbonate in about0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pumpinhibitor. In yet another embodiment, the antacid comprises a mixture ofsodium bicarbonate and magnesium hydroxide, wherein the sodiumbicarbonate and magnesium hydroxide are each present in about 0.1 mEq/mgproton pump inhibitor to about 5 mEq/mg proton pump inhibitor. In stillanother embodiment, the antacid comprises a mixture of sodiumbicarbonate, calcium carbonate, and magnesium hydroxide, wherein thesodium bicarbonate, calcium carbonate, and magnesium hydroxide are eachpresent in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg ofthe proton pump inhibitor.

In various other embodiments of the present invention, the antacid ispresent in an amount of about 0.1 mEq/mg to about 5 mEq/mg of the protonpump inhibitor, or about 0.5 mEq/mg to about 3 mEq/mg of the proton pumpinhibitor, or about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pumpinhibitor, or about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pumpinhibitor, or about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pumpinhibitor, or about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pumpinhibitor, or at least 0.5 mEq/mg of the proton pump inhibitor.

In other embodiments, the antacid is present in the pharmaceuticalformulations of the present invention in an from about 5 to about 50 mEqof antacid. In other embodiments, the antacid is present in thepharmaceutical formulations of the present invention in an amount fromabout 5 to about 40 mEq of antacid. In other embodiments, the antacid ispresent in the pharmaceutical formulations of the present invention inan amount from about 10 to about 30 mEq of antacid. In otherembodiments, the antacid is present in the pharmaceutical formulationsof the present invention in an amount from about 10 to about 20 mEq ofantacid. In other embodiments, the antacid is present in thepharmaceutical formulations of the present invention in an amount fromabout 5 to about 15 mEq of antacid.

In another embodiment, the antacid is present in the pharmaceuticalformulations of the present invention in an amount of about 0.1 mEq toabout 15 mEq/mg of proton pump inhibitor, or about 0.1 mEq/mg of protonpump inhibitor, or about 0.5 mEq/mg of proton pump inhibitor, or about 1mEq/mg of proton pump inhibitor, or about 2 mEq/mg of proton pumpinhibitor, or about 2.5 mEq/mg of proton pump inhibitor, or about 3mEq/mg of proton pump inhibitor, or about 3.5 mEq/mg of proton pumpinhibitor, or about 4 mEq/mg of proton pump inhibitor, or about 4.5mEq/mg of proton pump inhibitor, or about 5 mEq/mg of proton pumpinhibitor, or about 6 mEq/mg of proton pump inhibitor, or about 7 mEq/mgof proton pump inhibitor, or about 8 mEq/mg of proton pump inhibitor, orabout 9 mEq/mg of proton pump inhibitor, or about 10 mEq/mg of protonpump inhibitor, or about 11 mEq/mg of proton pump inhibitor, or about 12mEq/mg of proton pump inhibitor, or about 13 mEq/mg of proton pumpinhibitor, or about 14 mEq/mg of proton pump inhibitor, or about 15mEq/mg of proton pump inhibitor.

In one embodiment, the antacid is present in the pharmaceuticalformulations of the present invention in an amount of about 1 mEq toabout 160 mEq per dose, or about 1 mEq, or about 5 mEq, or about 10 mEq,or about 15 mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, orabout 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, orabout 60 mEq, or about 70 mEq, or about 80 mEq, or about 90 mEq, orabout 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, orabout 140 mEq, or about 150 mEq, or about 160 mEq per dose.

In another embodiment, the antacid is present in an amount of more thanabout 5 times, or more than about 10 times, or more than about 20 times,or more than about 30 times, or more than about 40 times, or more thanabout 50 times, or more than about 60 times, or more than about 70times, or more than about 80 times, or more than about 90 times, or morethan about 100 times the amount of the proton pump inhibiting agent on aweight to weight basis in the composition.

In another embodiment, the amount of antacid present in thepharmaceutical formulation is between 200 and 3500 mg. In otherembodiments, the amount of antacid present in the pharmaceuticalformulation is about 200 mgs, or about 300 mgs, or about 400 mgs, orabout 500 mgs, or about 600 mgs, or about 700 mgs, or about 800 mgs, orabout 900 mgs, or about 1000 mgs, or about 1100 mgs, or about 1200 mgs,or about 1300 mgs, or about 1400 mgs, or about 1500 mgs, or about 1600mgs, or about 1700 mgs, or about 1800 mgs, or about 1900 mgs, or about2000 mgs, or about 2100 mgs, or about 2200 mgs, or about 2300 mgs, orabout 2400 mgs, or about 2500 mgs, or about 2600 mgs, or about 2700 mgs,or about 2800 mgs, or about 2900 mgs, or about 3000 mgs, or about 3200mgs, or about 3500 mgs.

In some embodiments, if the at least one buffering agent is acombination of two or more buffering agents, the combination comprisesat least two non-amino acid buffering agents, wherein the combination ofat least two non-amino acid buffering agents comprises substantially noaluminum hydroxide-sodium bicarbonate co-precipitate. In otherembodiments, if the pharmaceutical composition comprises an amino acidbuffering agent, the total amount of buffering agent present in thepharmaceutical composition is less than about 5 mEq, or less than about4 mEq, or less than about 3 mEq. The phrase “amino acid buffering agent”as used herein includes amino acids, amino acid salts, and amino acidalkali salts. including: glycine, alanine, threonine, isoleucine,valine, phenylalanine, glutamic acid, asparagininic acid, lysine,aluminum glycinate and/or lysine glutamic acid salt, glycinehydrochloride, L-alanine, DL-alanine, L-threonine, DL-threonine,L-isoleucine, L-valine, L-phenylalanine, L-glutamic acid, L-glutamicacid hydrochloride, L-glutamic acid sodium salt, L-asparaginic acid,L-asparaginic acid sodium salt, L-lysine and L-lysine-L-glutamic acidsalt. The term “non-amino acid buffering agent” herein includesbuffering agents as defined hereinabove but does not include amino acidbuffering agents.

In other embodiments, the pharmaceutical composition comprisessubstantially no or no poly[phosphoryl/sulfon]-ated carbohydrate and isin the form of a solid dosage unit. In still another related embodiment,if such a composition comprises a poly[phosphoryl/sulfon]-atedcarbohydrate (e.g. sucralfate or sucrose octasulfate), the weight ratioof poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is lessthan 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is presentin the composition, if at all, in an amount less than 50 mg, less than25 mg, less than 10 mg or less than 5 mg.

Also provided herein are pharmaceutical formulations comprising at leastone soluble antacid. For example, in one embodiment, the antacid issodium bicarbonate and is present in about 0.1 mEq/mg proton pumpinhibitor to about 5 mEq/mg proton pump inhibitor. In anotherembodiment, the antacid is a mixture of sodium bicarbonate and magnesiumhydroxide, wherein the sodium bicarbonate and magnesium hydroxide areeach present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mgproton pump inhibitor. The term “soluble antacid” as used herein refersto an antacid that has a solubility of at least 500 mg/mL, or 300 mg/mL,or 200 mg/mL, or 100 mL/mL in the gastrointestinal fluid.

In some embodiments of the present invention, the antacid is a specificparticle size. For example, the average particle size of the antacid maybe no greater than 20 μm, or no greater than 30 μm, or no greater than40 μm, or no greater than 50 μm, or no greater than 60 μm, or no greaterthan 70 μm, or no greater than 80 μm, or no greater than 90 μm or nogreater than 100 μm in diameter. In various embodiments, at least about70% of the antacid is no greater than 20 μm, or no greater than 30 μm,or no greater than 40 μm, or no greater than 50 μm, or no greater than60 μm, or no greater than 70 μm, or no greater than 80 μm, or no greaterthan 90 μm or no greater than 100 μm in diameter. In other embodiments,at least about 85% of the antacid is no greater than 20 μm, or nogreater than 30 μm, or no greater than 40 μm, or no greater than 50 μm,or no greater than 60 μm, or no greater than 70 μm, or no greater than80 μm, or no greater than 90 μm or no greater than 100 μm in diameter.

Particle size of the buffer, especially that an insoluble buffer canaffect the onset of in-vivo neutralization of the stomach acid. Sincedecreased particle size increases in surface area, the particle sizereduction provides an increase in the rate of acid neutralization,leading to superior protection of PPI from gastric acid degradation. Onthe other hand, extremely fine particle size of buffer will result inthe powder mixture that is difficult to manufacture in commercial scaledue to their poor flow and difficulties in processing (i.e., compressionand encapsulation).

In various embodiments of the present invention, the antacid ismicronized. In some embodiments, particle size of at least 90% ofantacid (D₉₀) is less than about 300 μm, or less than about 250 μm, orless than about 200 μm, or less than about 150 μm, or less than about100 μm. In other embodiments, at least 75% of the antacid (D₇₅) hasparticle size of less than about 300 μm, or less than about 250 μm, orless than about 200 μm, or less than about 150 μm, or less than about100 μm. In still other embodiments, at least 50% of the antacid (D₅₀)has particle size of less than about 300 μm, or less than about 250 μm,or less than about 200 μm, or less than about 150 μm, or less than about100 μm.

Spray dried antacid can also facilitate the speed of neutralization byfast reacting with acid upon contact. Sprayed dried antacid typicallyhas spherical particle shape which aids with achieving homogeneous blendduring manufacturing process. In one embodiment the antacid is spraydried with at least 15% of coating material such as maltodextrin orstarch. In still other embodiment the antacid is spray dried with atleast 10% of coating material such as maltodextrin or starch. Yetanother embodiment the antacid is spray dried with at least 15% ofcoating material such as maltodextrin or starch.

Kinetic Stomach Model

The acid neutralizing capacity and pH profile of various antacidcombinations can be evaluated by using an in-vitro stomach model.Several of these simulated dynamic models are known in the art. See,e.g., Smyth et al., Correlation of In-Vivo Methodology for Evaluation ofAntacids, J. Pharm. Sci. Vol. 65, 1045 (1976); Hobert, Fordham et al.,In-Vivo Evaluation of Liquid Antacids, New England Journal of Med. 288,923 (1973); Johnson et al., The Chemical Testing of Antacids, Gut 5, 585(1964); Clain et al., In-Vitro Neutralizing Capacity of CommerciallyAvailable Antacid Mixtures and Their Role in the Treatment of PepticUlcer, S. Afr. Med. J., 57, 158 (1980); Rossett et al., In-VitroEvaluation of Efficacy of More Frequently Used Antacids with ParticularAttention to Tablets, Gastroentrology, 26, 490; Decktor et al.,Comparative Effects of Liquid Antacids on Esophageal and Gastric pH inPatients with Heartburn, Am. J. of Therapeutics, 2, 481 (1995); CharlesFuchs, Antacids: Their Function, Formulation and Evaluation, Drug andCosmetic Industry, 49, 692; Stewart M. Beekman, Preparation andProperties of New Gastric Antacids I, Aluminium Hydroxide-MagnesiumCarbonate Dried Gels, J. Am. Pharm. Assoc., 49, 191 (1960). For example,a modified Fuch's model where the continuous influx of 0.5 mEq of acidis added to initial 5.0 mEq of acid to simulate a fasting state ofstomach can be used with the present invention.

In various embodiments of the present invention, the antacid increasesthe gastric pH to at least about 3.5 for no more than about 90 minutesas measured by a simulated stomach model such as Fuch's kinetic in-vitropH model. In other embodiments, the antacid increases the pH to at leastabout 3.5 for no more than about 60 minutes. In still other embodiments,the antacid increases the pH to at least about 3.5 for no more than 45minutes. Depending on the buffer system used (i.e., type of antacid andamount) some embodiments of the present invention, the antacid increasesthe gastric pH to at least about 3.5 for no more than about 30 minutesas measured by a simulated stomach model such as Fuchs' kinetic in-vitropH model. In other embodiments, the antacid increases the gastric pH toat least about 3.5 for less than about 25 minutes as measured by asimulated stomach model such as Fuch's kinetic in-vitro pH model. In yetother embodiments, the antacid increases the gastric pH to at leastabout 3.5 for less than about 20 minutes, or less than about 15 minutes,or less than about 10 minutes as measured by a stimulated stomach modelsuch as Fuch's kinetic in-vitro pH model. In each of these embodiments,the antacid protects at least some of the proton pump inhibitor and atherapeutically effective amount of the proton pump inhibitor isdelivered to the subject.

In each of these embodiments, the antacid protects at least some of theproton pump inhibitor and a therapeutically effective amount of theproton pump inhibitor is delivered to the subject.

Disintegrants

Most PPIs are sparingly soluble in water and therefore exhibit acorrelation of disintegration time to bioavailability. Thus, it isimportant to optimize the disintegration time in order to enhance invivo dissolution of the drug. In order to release the active ingredientfrom a solid dosage form matrix as efficiently as possible, disintegrantis often used in the formulation, especially when the dosage forms arecompressed with binder. Disintegrants help rupturing the dosage formmatrix by swelling or capillary action when moisture is absorbed intothe dosage form. Starch is the oldest disintegrants and 5-15% level issuggested (Remington, 20th Ed, p 862). Super disintegrants such asAc-di-Sol or Crospovidones are effective at lower levels (2-4%).

Ac-Di-Sol is effective in both direct compression and wet granulationformulations. The amount of Ac-Di-Sol used in direct compressiontableting may vary with typical usage levels between 1 and 3 percent.When added to granulations, generally the same percent is used as with adirect compression formulation. It is often added to both the wet massand the dried granulations before compression. As with directcompression, the use level typically ranges from 1 to 3 percent withhalf of the material added to the wet mass and half added to the runningpowder. This promotes disintegration of both the granules and thetablet.

The amount of Ac-Di-Sol used in capsule formulations generally rangesfrom 4-6 percent. Reduced interparticle contact within a capsulefacilitates the need for elevated levels of disintegrant. Capsulesfilled on automatic dosater types of equipment, as opposed tosemi-automatic or hand-filled machines, are more dense and have a harderstructure due to the greater compressional forces needed to form theplug and successfully transfer it into the gelatin shell. Greater plughardness results in greater effectiveness of Ac-Di-Sol.

Solid Oral Dosage Forms

In some embodiments of the present invention, the pharmaceuticalformulation has greater than about 1 wt-% of a disintegrant. In variousembodiments of the present invention, the pharmaceutical formulationshave between about 1 wt-% to about 11 wt-% or between about 1 wt-% toabout 8 wt-%, or about 1 wt-% to about 6 wt-%, or about 1 wt-% to about4 wt-%, of a disintegrant. In some embodiments the disintegrant isAc-Di-Sol. In other embodiments the disintegrant is sodium starchglycolated such as Promogel® or Explotab®. In still other embodiments,the pharmaceutical formulations have between about 2 wt-% to about 8wt-% disintegrant, or between about 2 wt-% to about 6 wt-%, or betweenabout 2 wt-% to about 4 wt-%. In yet other embodiments, thepharmaceutical formulations have greater than about 2 wt-% disintegrant.

Because sodium bicarbonate has effervescent characteristic when mixedwith acid such as gastric fluid, some embodiments of the pharmaceuticalformulations of the present invention can comprise at least about 400mgs of sodium bicarbonate and greater than about 1 wt-% of adisintegrant. In some embodiments, the pharmaceutical formulationcomprises about 2 wt-% disintegrant, or about 3 wt-% disintegrant, orabout 4 wt-% disintegrant. In yet other embodiments, the pharmaceuticalformulation comprises less than 8 wt-% disintegrant. In otherembodiments, the pharmaceutical formulations have less than about 5 wt-%disintegrant, or less than about 4 wt-% disintegrant, or less than about3 wt-% disintegrant, or less than about 2 wt-% disintegrant, or lessthan about 1 wt-% disintegrant. In other embodiments, the sodiumbicarbonate helps facilitate the disintegration of the capsule product.

Because sodium bicarbonate has effervescent characteristic when mixedwith acid such as gastric fluid, some embodiments of the pharmaceuticalformulations of the present invention can comprise at least about 200mgs of sodium bicarbonate and greater than about 1 wt-% of adisintegrant. In some embodiments, the pharmaceutical formulationcomprises about 2 wt-% disintegrant, or about 3 wt-% disintegrant, orabout 4 wt-% disintegrant. In yet other embodiments, the pharmaceuticalformulation comprises less than 8 wt-% disintegrant. In otherembodiments, the pharmaceutical formulations have less than about 5 wt-%disintegrant, or less than about 4 wt-% disintegrant, or less than about3 wt-% disintegrant, or less than about 2 wt-% disintegrant, or lessthan about 1 wt-% disintegrant. In other embodiments, the sodiumbicarbonate helps facilitate the disintegration of the capsule product.

In some embodiments of the present invention, the wt-% of disintegrantcan be decreased and the amount of sodium bicarbonate increased toachieve the desired bioavailability of the proton pump inhibitor. Inother embodiments, the wt-% of disintegrant can be increased and theamount of sodium bicarbonate decreased to achieve the desiredbioavailability of the proton pump inhibitor.

Binders

Binders impart a cohesiveness to solid oral dosage form formulations:for powder filled capsule formulation, they aid in plug formation thatcan be filled into a hard sell capsules and for tablet formulation, theyensure the tablet remaining intact after compression. Materials commonlyused as binders include starch gelatin, and sugars such as sucrose,glucose, dextrose, molasses, and lactose. The quantity of binder usedinfluences the characteristics of the dosage form and/or manufacturingprocesses. For example, dosator type encapsulators (e.g. Zanasi machine)normally requires the filling material to be mechanically strong plugswhereas dosing disc type encapsulators (e.g., HK machine) do not requirethe same degree of high plug breaking force. In general, binder level of1-10% are used in powder-filled hard gel capsule formulations. Binderusage level in tablet formulations varies whether direct compression,wet granulation, or usage of other excipients such as fillers whichitself can act as moderate binder. Formulators skilled in art candetermine the binder level for the formulations, but binder usage levelof 2-25% in tablet formulations is common.

In some embodiments of the present invention, the wt-% of thedisintegrant is at least equivalent to the wt-% of the binder. Forexample, formulations of the present invention may comprise about 5 wt-%of disintegrant and about 2 wt-% of a binder or about 3 wt-% of adisintegrant and about 3 wt-% of a binder. In other embodiments, thesolid oral dosage form does not comprise a binder. In some embodiments,the solid oral dosage form comprises significantly more disintegrantthan binder. For example, the binder may be present in an amount of lessthan 2 wt-% while the disintegrant is present in an amount of greaterthan 5 wt-%. In other embodiments, the binder and disintegrant arepresent in the formulation in substantially the same amount. Forexample, the binder may be present in an amount of about 2 wt-% and thedisintegrant may be present in an amount of about 3 wt-%.

Microencapsulation

In accordance with one aspect of the present invention, compositions mayinclude microencapsulation of the proton pump inhibitor or the antacid,in order to enhance the shelf life of the composition and/or enhance thetaste of the pharmaceutical composition. See U.S. application Ser. No.10/893,203, filed Jul. 16, 2004, which claims priority to U.S.Provisional Application No. 60/488,321 filed Jul. 18, 2003, both ofwhich are incorporated by reference in their entirety.

Materials useful for enhancing the shelf life and/or masking the tasteof the pharmaceutical compositions of the present invention includematerials compatible with the proton pump inhibitor of thepharmaceutical compositions which sufficiently isolate the proton pumpinhibitor from other non-compatible excipients. Materials compatiblewith the proton pump inhibitors of the present invention are those thatenhance the shelf life of the proton pump inhibitor, i.e., by slowing orstopping degradation of the proton pump inhibitor.

Exemplary microencapsulation materials useful for enhancing the shelflife of pharmaceutical compositions comprising a proton pump inhibitorinclude, but are not limited to: hydroxypropyl cellulose ethers (HPC)such as Klucel® or Nisso HPC; low-substituted hydroxypropyl celluloseethers (L-HPC); hydroxypropyl methyl cellulose ethers (HPMC) such asSeppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS,PrimaFlo, Benecel MP824, and Benecel MP843; methylcellulose polymerssuch as Methocel®-A and Metolose®; Ethylcelluloses (EC) and mixturesthereof such as E461, Ethocel®, Aqualon®-EC, Surelease®; Polyvinylalcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such asNatrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses(CMC) such as Aqualon®-CMC; polyvinyl alcohol and polyethylene glycolco-polymers such as Kollicoat IR®; monoglycerides (Myverol),triglycerides (KLX), polyethylene glycols, modified food starch, acrylicpolymers and mixtures of acrylic polymers with cellulose ethers such asEudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetatephthalate; sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins; and mixtures of these materials.

In various embodiments, an antacid such as sodium bicarbonate or sodiumcarbonate is incorporated into the microencapsulation material. In otherembodiments, an antioxidant such as BHT is incorporated into themicroencapsulation material. In still other embodiments, plasticizerssuch as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450,PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, andtriacetin are incorporated into the microencapsulation material. Inother embodiments, the microencapsulating material useful for enhancingthe shelf life of the pharmaceutical compositions is from the USP or theNational Formulary (NF). In yet other embodiments, themicroencapsulation material is Klucel. In still other embodiments, themicroencapsulation material is methocel.

In further embodiments, one or more other compatible materials arepresent in the microencapsulation material. Exemplary materials include,but are not limited to, pH modifiers, parietal cell activators, erosionfacilitators, diffusion facilitators, anti-adherents, anti-foamingagents, antioxidants, flavoring agents, and carrier materials such asbinders, suspending agents, disintegration agents, filling agents,surfactants, solubilizers, stabilizers, lubricants, wetting agents, anddiluents.

According to one aspect of the invention, some of the proton pumpinhibitor is coated. The coating may be, for example, a gastricresistant coating such as an enteric coating (See, e.g, WO 91/16895 andWO 91/16886), a controlled-release coating, an enzymatic-controlledcoating, a film coating, a sustained-release coating, animmediate-release coating, or a delayed-release coating. According toanother aspect of the invention, the coating may be useful for enhancingthe stability of the pharmaceutical compositions of the presentinvention.

In addition to microencapsulating the proton pump inhibitors with amaterial as described herein, the pharmaceutical compositions of thepresent invention may also comprise one or more flavoring agents. Insome embodiments, one or more flavoring agents are mixed with thetaste-masking material prior to microencapsulating the proton pumpinhibitor and/or antacid. In other embodiments, the flavoring agent ismixed with non-compatible excipients during the formulation process andis therefore not in contact with the proton pump inhibitor and/orantacid, and not part of the microencapsulation material.

“Flavoring agents” or “sweeteners” useful in the pharmaceuticalcompositions of the present invention include, e.g., acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose,tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wildcherry, wintergreen, xylitol, or any combination of these flavoringingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint,menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Inother embodiments, sodium chloride is incorporated into thepharmaceutical composition. Based on the proton pump inhibitor, antacid,and excipients, as well as the amounts of each one, one of skill in theart would be able to determine the best combination of flavors toprovide the optimally flavored product for consumer demand andcompliance. See, e.g., Roy et al., Modifying Bitterness: Mechanism,Ingredients, and Applications (1997).

Methods of Microencapsulation

The proton pump inhibitor and/or antacid may be microencapsulated bymethods known by one of ordinary skill in the art. Such known methodsinclude, e.g., spray drying processes, spinning disk-solvent processes,hot melt processes, spray chilling methods, fluidized bed, electrostaticdeposition, centrifugal extrusion, rotational suspension separation,polymerization at liquid-gas or solid-gas interface, pressure extrusion,or spraying solvent extraction bath. In addition to these, severalchemical techniques, e.g., complex coacervation, solvent evaporation,polymer-polymer incompatibility, interfacial polymerization in liquidmedia, in situ polymerization, in-liquid drying, and desolvation inliquid media could also be used.

The spinning disk method allows for: 1) an increased production rate dueto higher feed rates and use of higher solids loading in feed solution,2) the production of more spherical particles, 3) the production of amore even coating, and 4) limited clogging of the spray nozzle duringthe process.

Spray drying is often more readily available for scale-up. In variousembodiments, the material used in the spray-dry encapsulation process isemulsified or dispersed into the core material in a concentrated form,e.g., 10-60% solids. The microencapsulation material is, in oneembodiment, emulsified until about 1 to 3 μm droplets are obtained. Oncea dispersion of proton pump inhibitor and encapsulation material areobtained, the emulsion is fed as droplets into the heated chamber of thespray drier. In some embodiments, the droplets are sprayed into thechamber or spun off a rotating disk. The microspheres are then dried inthe heated chamber and fall to the bottom of the spray drying chamberwhere they are harvested.

In some embodiments of the present invention, the microspheres haveirregular geometries. In other embodiments, the microspheres areaggregates of smaller particles.

In various embodiments, the proton pump inhibitor and/or antacid arepresent in the microspheres in an amount greater than 1%, greater than2.5%, greater than 5%, greater than 10%, greater than 15%, greater than20%, greater than 25%, greater than 30%, greater than 35%, greater than40%, greater than 45%, greater than 50%, greater than 55%, greater than60%, greater than 65%, greater than 70%, greater than 75%, greater than80%, greater than 85%, greater than 90% greater than 95% or greater than98% weight percent of the proton pump inhibitor to themicroencapsulation material used to enhance the stability of thepharmaceutical composition or the taste-masking material.

Stability

A pharmaceutical formulation of the present invention is stable if,e.g., the proton pump inhibitor has less than about 0.5% degradationafter one month of storage at room temperature, or less than about 1%degradation after one month at room temperature, or less than about 1.5%degradation after one month of storage at room temperature, or less thanabout 2% degradation after one month storage at room temperature, orless than about 2.5% degradation after one month of storage at roomtemperature, or less than about 3% degradation after one month ofstorage at room temperature.

In other embodiments, a pharmaceutical formulation of the presentinvention may have stable if the pharmaceutical formulation containsless than about 5% total impurities after about 3 years of storage, orafter about 2.5 years of storage, or about 2 years of storage, or about1.5 years of storage, or about 1 year of storage, or after 11 months ofstorage, or after 10 months of storage, or after 9 months of storage, orafter 8 months of storage, or after 7 months of storage, or after 6months of storage, or after 5 months of storage, or after 4 months ofstorage, or after 3 months of storage, or after 2 months of storage, orafter 1 month of storage.

In further embodiments, pharmaceutical formulations of the presentinvention may contain microencapsulated omeprazole and have enhancedshelf life stability if the pharmaceutical formulation contains lessdegradation of the proton pump inhibitor than proton pump inhibitor inthe same formulation which is not microencapsulated, or “bare”. Forexample, if bare proton pump inhibitor in the pharmaceutical formulationdegrades at room temperature by more than about 2% after one month ofstorage and the microencapsulated material degrades at room temperatureby less than about 2% after one month of storage, then the proton pumpinhibitor has been microencapsulated with a compatible material thatenhances the shelf life of the pharmaceutical formulation.

Dosage

The proton pump inhibiting agent is administered and dosed in accordancewith good medical practice, taking into account the clinical conditionof the individual patient, the site and method of administration,scheduling of administration, and other factors known to medicalpractitioners. In human therapy, it is important to provide a dosageform that delivers the required therapeutic amount of the therapeuticagent in vivo, and renders therapeutic agent bioavailable in a rapidmanner. In addition to the dosage forms described herein, the dosageforms described by Phillips et al. in U.S. Pat. Nos. 5,840,737,6,489,346, 6,699,885 and 6,645,988 are incorporated herein by reference.

The percent of intact drug that is absorbed into the bloodstream is notnarrowly critical, as long as a therapeutically effective amount, e.g.,a gastrointestinal-disorder-effective amount of a proton pump inhibitingagent, is absorbed following administration of the pharmaceuticalcomposition to a subject. Gastrointestinal-disorder-effective amountsmay be found in U.S. Pat. No. 5,622,719. It is understood that theamount of proton pump inhibiting agent and/or antacid that isadministered to a subject is dependent on a number of factors, e.g., thesex, general health, diet, and/or body weight of the subject.

Illustratively, administration of a substituted bicyclic aryl-imidazoleto a young child or a small animal, such as a dog, a relatively lowamount of the proton pump inhibitor, e.g., about 1 mg to about 30 mg,will often provide blood serum concentrations consistent withtherapeutic effectiveness. Where the subject is an adult human or alarge animal, such as a horse, achievement of a therapeuticallyeffective blood serum concentration will require larger dosage units,e.g., about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg,about 80 mg, or about 120 mg dose for an adult human, or about 150 mg,or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mgdose, or about 1500 mg dose, or about 2000 mg dose, or about 2500 mgdose, or about 3000 mg dose or about 3200 mg dose or about 3500 mg dosefor an adult horse.

In various other embodiments of the present invention, the amount ofproton pump inhibitor administered to a subject is, e.g., about 0.5-2mg/Kg of body weight, or about 0.5 mg/Kg of body weight, or about 1mg/Kg of body weight, or about 1.5 mg/Kg of body weight, or about 2mg/Kg of body weight.

Treatment dosages generally may be titrated to optimize safety andefficacy. Typically, dosage-effect relationships from in vitro and/or invivo tests initially can provide useful guidance on the proper doses forsubject administration. In terms of treatment protocols, it should beappreciated that the dosage to be administered will depend on severalfactors, including the particular agent that is administered, the routechosen for administration, and the condition of the particular subject.

In various embodiments, unit dosage forms for humans contain about 1 mgto about 120 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about15 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg,or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about100 mg, or about 110 mg, or about 120 mg of a proton pump inhibitor.

In a further embodiment of the present invention, the pharmaceuticalcomposition is administered in an amount to achieve a measurable serumconcentration of a non-acid degraded proton pump inhibiting agentgreater than about 100 ng/ml within about 30 minutes afteradministration of the pharmaceutical composition. In another embodimentof the present invention, the pharmaceutical composition is administeredto the subject in an amount to achieve a measurable serum concentrationof a non-acid degraded or non-acid reacted proton pump inhibiting agentgreater than about 100 ng/ml within about 15 minutes afteradministration of the pharmaceutical composition. In yet anotherembodiment, the pharmaceutical composition is administered to thesubject in an amount to achieve a measurable serum concentration of anon-acid degraded or non-acid reacted proton pump inhibiting agentgreater than about 100 ng/ml within about 10 minutes afteradministration of the pharmaceutical composition.

In another embodiment of the present invention, the composition isadministered to the subject in an amount to achieve a measurable serumconcentration of the proton pump inhibiting agent greater than about 150ng/ml within about 15 minutes and to maintain a serum concentration ofthe proton pump inhibiting agent of greater than about 150 ng/ml fromabout 15 minutes to about 1 hour after administration of thecomposition. In yet another embodiment of the present invention, thecomposition is administered to the subject in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 250 ng/ml within about 15 minutes and to maintain aserum concentration of the proton pump inhibiting agent of greater thanabout 250 ng/ml from about 15 minutes to about 1 hour afteradministration of the composition. In another embodiment of the presentinvention, the composition is administered to the subject in an amountto achieve a measurable serum concentration of the proton pumpinhibiting agent greater than about 350 ng/ml within about 15 minutesand to maintain a serum concentration of the proton pump inhibitingagent of greater than about 350 ng/ml from about 15 minutes to about 1hour after administration of the composition. In another embodiment ofthe present invention, the composition is administered to the subject inan amount to achieve a measurable serum concentration of the proton pumpinhibiting agent greater than about 450 ng/ml within about 15 minutesand to maintain a serum concentration of the proton pump inhibitingagent of greater than about 450 ng/ml from about 15 minutes to about 1hour after administration of the composition.

In another embodiment of the present invention, the composition isadministered to the subject in an amount to achieve a measurable serumconcentration of the proton pump inhibiting agent greater than about 150ng/ml within about 30 minutes and to maintain a serum concentration ofthe proton pump inhibiting agent of greater than about 150 ng/ml fromabout 30 minutes to about 1 hour after administration of thecomposition. In yet another embodiment of the present invention, thecomposition is administered to the subject in an amount to achieve ameasurable serum concentration of the proton pump inhibiting agentgreater than about 250 ng/ml within about 30 minutes and to maintain aserum concentration of the proton pump inhibiting agent of greater thanabout 250 ng/ml from about 30 minutes to about 1 hour afteradministration of the composition. In another embodiment of the presentinvention, the composition is administered to the subject in an amountto achieve a measurable serum concentration of the proton pumpinhibiting agent greater than about 350 ng/ml within about 30 minutesand to maintain a serum concentration of the proton pump inhibitingagent of greater than about 350 ng/ml from about 30 minutes to about 1hour after administration of the composition. In another embodiment ofthe present invention, the composition is administered to the subject inan amount to achieve a measurable serum concentration of the proton pumpinhibiting agent greater than about 450 ng/ml within about 30 minutesand to maintain a serum concentration of the proton pump inhibitingagent of greater than about 450 ng/ml from about 30 minutes to about 1hour after administration of the composition.

In still another embodiment of the present invention, the composition isadministered to the subject in an amount to achieve a measurable serumconcentration of a non-acid degraded or non-acid reacted proton pumpinhibiting agent greater than about 500 ng/ml within about 1 hour afteradministration of the composition. In yet another embodiment of thepresent invention, the composition is administered to the subject in anamount to achieve a measurable serum concentration of a non-aciddegraded or non-acid reacted proton pump inhibiting agent greater thanabout 300 ng/ml within about 45 minutes after administration of thecomposition.

In another embodiment of the present invention, the composition isadministered to the subject in an amount sufficient to achieve a maximumserum concentration (Cmax) at a time (Tmax) that is within about 90, 70,60, 50, 40, 30 or 20 minutes after administration of the compositionaccording to the present invention.

In still another embodiment of the invention, the composition isadministered to the subject in an amount sufficient to achieve a maximumserum concentration (Cmax) at a time (Tmax) that is between about 10 andabout 90 minutes, between about 10 to about 60 minutes, between about 15to about 60 minutes or between about 20 to about 60 minutes afteradministration of the composition according to the present invention. Insome specific embodiments, the values of Cmax and Tmax are averages overa test population. In other specific embodiments, the values of Cmax andTmax are the values for an individual.

In still another embodiment, the composition is administered in anamount sufficient to achieve a maximum serum concentration (Cmax) offrom about 400 to about 2000 ng/mL, from about 400 to about 1500 ng/mL,from about 1000 to about 1500 ng/mL, from about 400 to about 1000 ng/mLor from about 400 to about 700 ng/mL. In some specific embodiments, thevalues of Cmax and Tmax are averages over a test population. In otherspecific embodiments, the values of Cmax and Tmax are the values for anindividual.

In a further embodiment, the composition is administered in an amountsufficient to achieve a maximum serum concentration (Cmax) of greaterthan 400 ng/mL, greater than 600 ng/mL, greater than 1000 ng/mL. In somespecific embodiments, the values of Cmax and Tmax are averages over atest population. In other specific embodiments, the values of Cmax andTmax are the values for an individual.

In one embodiment of the present invention, the composition isadministered to a subject in a gastrointestinal-disorder-effectiveamount, that is, the composition is administered in an amount thatachieves a therapeutically-effective dose of a proton pump inhibitingagent in the blood serum of a subject for a period of time to elicit adesired therapeutic effect. Illustratively, in a fasting adult human(fasting for generally at least 10 hours) the composition isadministered to achieve a therapeutically-effective dose of a protonpump inhibiting agent in the blood serum of a subject within about 45minutes after administration of the composition. In another embodimentof the present invention, a therapeutically-effective dose of the protonpump inhibiting agent is achieved in the blood serum of a subject withinabout 30 minutes from the time of administration of the composition tothe subject. In yet another embodiment, a therapeutically-effective doseof the proton pump inhibiting agent is achieved in the blood serum of asubject within about 20 minutes from the time of administration to thesubject. In still another embodiment of the present invention, atherapeutically-effective dose of the proton pump inhibiting agent isachieved in the blood serum of a subject at about 15 minutes from thetime of administration of the composition to the subject.

In further embodiments, the oral bioavailability of the proton pumpinhibitor is at least about 25%. In other embodiments, the oralbioavailability of the proton pump inhibitor is at least about 30%. Instill other embodiments, the oral bioavailability of the proton pumpinhibitor is at least 35%, or at least 40%, or at least 45%, or at least50%, or at least 55% bioavailable, or at least 60%.

In alternative embodiments, the pharmaceutical composition comprises atleast about 5 mEq of antacid and is bioequivalent to a proton pumpinhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, orAciphex®. In other embodiments, the pharmaceutical composition comprisesbetween about 5 mEq to about 30 mEq of antacid and is bioequivalent to aproton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®,Protonic®, or Aciphex®. In still other embodiments, the pharmaceuticalcomposition comprises between about mEq to about 30 mEq, or about 5 mEq,or about 7 mEq, or about 10 mEq, or about 13 mEq, or about 15 mEq, orabout 17 mEq, or about 20 mEq, or about 22 mEq, or about 25 mEq, orabout 27 mEq, or about 30 mEq of antacid and is bioequivalent to aproton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®,Protonic®, or Aciphex®. “Bioequivalent” is intended to mean that thearea under the serum concentration time curve (AUC) and the peak serumconcentration (C_(max)) are each within 80% and 120%.

In alternative embodiments, the pharmaceutical composition comprises atleast about 5 mEq of antacid and is bioequivalent to a proton pumpinhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, orAciphex®. In other embodiments, the pharmaceutical composition comprisesbetween about 5 mEq to about 11 mEq of antacid and is bioequivalent to aproton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®,Protonic®, or Aciphex®. In still other embodiments, the pharmaceuticalcomposition comprises between about 5 mEq to about 11 mEq, or about 5mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, orabout 10 mEq, or about 11 mEq of antacid and is bioequivalent to aproton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®,Protonic®, or Aciphex®.

In other embodiments, when administered to a subject, the pharmaceuticalcomposition has an area under the serum concentration time curve (AUC)for the proton pump inhibitor that is equivalent to the area under theserum concentration time curve (AUC) for the proton pump inhibitor whenthe enteric form of the proton pump inhibitor is delivered withoutantacid. “Equivalent” is intended to mean that the area under the serumconcentration time curve (AUC) for the proton pump inhibitor is within±30% of the area under the serum concentration time curve (AUC) when thesame dosage amount of the proton pump inhibitor is enterically coatedand delivered to the subject with less than 1 mEq of antacid. The“enteric form of the proton pump inhibitor” is intended to mean thatsome or most of the proton pump inhibitor has been enterically coated toensure that at least some of the drug is released in the proximal regionof the small intestine (duodenum), rather than the acidic environment ofthe stomach.

In yet other embodiments, the pharmaceutical compositions provide arelease profile of the proton pump inhibitor, using USP dissolutionmethods, whereby greater than about 50% of the proton pump inhibitor isreleased from the composition within about 2 hours; or greater than 50%of the proton pump inhibitor is released from the composition withinabout 1.5 hours; or greater than 50% of the proton pump inhibitor isreleased from the composition within about 1 hour after exposure togastrointestinal fluid. In another embodiment, greater than about 60% ofthe proton pump inhibitor is released from the composition within about2 hours; or greater than 60% of the proton pump inhibitor is releasedfrom the composition within about 1.5 hours; or greater than 60% of theproton pump inhibitor is released from the composition within about 1hour after exposure to gastrointestinal fluid. In yet anotherembodiment, greater than about 70% of the proton pump inhibitor isreleased from the composition within about 2 hours; or greater than 70%of the proton pump inhibitor is released from the composition withinabout 1.5 hours; or greater than 70% of the proton pump inhibitor isreleased from the composition within about 1 hour after exposure togastrointestinal fluid.

Compositions contemplated by the present invention provide a therapeuticeffect as proton pump inhibiting agent medications over an interval ofabout 5 minutes to about 24 hours after administration, enabling, forexample, once-a-day, twice-a-day, or three times a day administration ifdesired. Generally speaking, one will desire to administer an amount ofthe compound that is effective to achieve a serum level commensuratewith the concentrations found to be effective in vivo for a period oftime effective to elicit a therapeutic effect. Determination of theseparameters is well within the skill of the art.

Dosage Forms

The pharmaceutical compositions of the present invention contain desiredamounts of proton pump inhibitor and antacid and can be in the form of:a tablet, (including a suspension tablet, a chewable tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC) a lozenge, a sachet, atroche, pellets, granules, or an aerosol. The pharmaceuticalcompositions of the present invention can be manufactured byconventional pharmacological techniques.

In some embodiments, the pharmaceutical compositions of the presentinvention contain desired amounts of proton pump inhibiting inhibitorand antacid and are in a solid dosage form. In other embodiments, thepharmaceutical compositions of the present invention contain desiredamounts of proton pump inhibitor and antacid and are administered in theform of a capsule (including both soft or hard capsules, e.g., capsulesmade from animal-derived gelatineor plant-derived HPMC). Thepharmaceutical compositions of the present invention can be manufacturedby conventional pharmacological techniques.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., prilling, spray drying,pan coating, melt granulation, granulation, wurster coating, tangentialcoating, top spraying, extruding, coacervation and the like.

In one embodiment, the proton pump inhibitor is microencapsulated priorto being formulated into one of the above forms. In another embodiment,some of the proton pump inhibitor is microencapsulated prior to beingformulated. In another embodiment, some or all of the antacid ismicroencapsulated prior to being formulated. In still anotherembodiment, some or most of the proton pump inhibitor is coated prior tobeing further formulated by using standard coating procedures, such asthose described in Remington's Pharmaceutical Sciences, 20th Edition(2000). In yet other embodiments contemplated by the present invention,a film coating is provided around the pharmaceutical composition.

In other embodiments, the pharmaceutical compositions further compriseone or more additional materials such as a pharmaceutically compatiblecarrier, binder, filling agent, suspending agent, flavoring agent,sweetening agent, disintegrating agent, surfactant, preservative,lubricant, colorant, diluent, solubilizer, moistening agent, stabilizer,wetting agent, anti-adherent, parietal cell activator, anti-foamingagent, antioxidant, chelating agent, antifungal agent, antibacterialagent, or one or more combination thereof.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, e.g., diethyl phthalate, citrateesters, polyethylene glycol, glycerol, acetylated glycerides, triacetin,polypropylene glycol, polyethylene glycol, triethyl citrate, dibutylsebacate, stearic acid, stearol, stearate, and castor oil.

Exemplary Solid Oral Dosage Compositions

Solid oral dosage compositions, e.g., tablets, chewable tablets,effervescent tablets, caplets, and capsules, can be prepared, forexample, by mixing the proton pump inhibitor, one or more antacid, andpharmaceutical excipients to form a bulk blend composition. Whenreferring to these bulk blend compositions as homogeneous, it is meantthat the proton pump inhibitor and antacid are dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms, such as tablets,pills, and capsules. The individual unit dosages may also comprise filmcoatings, which disintegrate upon oral ingestion or upon contact withdiluent.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend compositions described above. In various embodiments,compressed tablets of the present invention will comprise one or morefunctional excipients such as binding agents and/or disintegrants. Inother embodiments, the compressed tablets will comprise a filmsurrounding the final compressed tablet. In other embodiments, thecompressed tablets comprise one or more excipients and/or flavoringagents.

A chewable tablet may be prepared by compacting bulk blend compositions,described above. In one embodiment, the chewable tablet comprises amaterial useful for enhancing the shelf life of the pharmaceuticalcomposition. In another embodiment, the microencapsulated material hastaste-masking properties. In various other embodiments, the chewabletablet comprises one or more flavoring agents and one or moretaste-masking materials. In yet other embodiments the chewable tabletcomprised both a material useful for enhancing the shelf life of thepharmaceutical formulation and one or more flavoring agents.

In various embodiments, the proton pump inhibitor, antacid, andoptionally one or more excipients, are dry blended and compressed into amass, such as a tablet or caplet, having a hardness sufficient toprovide a pharmaceutical composition that substantially disintegrateswithin less than about 30 minutes, less than about 35 minutes, less thanabout 40 minutes, less than about 45 minutes, less than about 50minutes, less than about 55 minutes, or less than about 60 minutes,after oral administration, thereby releasing the antacid and the protonpump inhibitor into the gastrointestinal fluid. When at least 50% of thepharmaceutical composition has disintegrated, the compressed mass hassubstantially disintegrated.

A capsule may be prepared by placing any of the bulk blend compositionsdescribed above, into a capsule. In some embodiments of the presentinvention, the therapeutic dose is split into multiple (e.g., two,three, or four) capsules. In some embodiments, the entire dose of theproton pump inhibitor and antacid are delivered in a capsule form. Forexample, the capsule may comprise between about 10 mg to about 120 mg ofa proton pump inhibitor and between about 5 mEq to about 30 mEq ofantacid. In some embodiments, the antacid may be selected from sodiumbicarbonate, magnesium hydroxide, calcium carbonate, magnesium oxide,and mixtures thereof. In alternative embodiments the capsule comprises 5mEq to about 30 mEq of sodium bicarbonate.

Exemplary Powder Compositions

A powder for suspension may be prepared by combining at least one acidlabile proton pump inhibitor and between about 5 mEq to about 11 mEq ofantacid. In various embodiments, the powder may comprise one or morepharmaceutical excipients and flavors. A powder for suspension may beprepared, for example, by mixing the proton pump inhibitor, one or moreantacids, and optional pharmaceutical excipients to form a bulk blendcomposition. This bulk blend is uniformly subdivided into unit dosagepackaging or multi-dosage packaging units. The term “uniform” means thehomogeneity of the bulk blend is substantially maintained during thepackaging process.

In some embodiments, some or all of the proton pump inhibitor ismicronized. Additional embodiments of the present invention alsocomprise a suspending agent and/or a wetting agent.

Effervescent powders are also prepared in accordance with the presentinvention. Effervescent salts have been used to disperse medicines inwater for oral administration. Effervescent salts are granules or coarsepowders containing a medicinal agent in a dry mixture, usually composedof sodium bicarbonate, citric acid and/or tartaric acid. When salts ofthe present invention are added to water, the acids and the base reactto liberate carbon dioxide gas, thereby causing “effervescence.”Examples of effervescent salts include, e.g., the following ingredients:sodium bicarbonate or a mixture of sodium bicarbonate and sodiumcarbonate, citric acid and/or tartaric acid. Any acid-base combinationthat results in the liberation of carbon dioxide can be used in place ofthe combination of sodium bicarbonate and citric and tartaric acids, aslong as the ingredients were suitable for pharmaceutical use and resultin a pH of about 6.0 or higher.

The method of preparation of the effervescent granules of the presentinvention employs three basic processes: wet granulation, drygranulation and fusion. The fusion method is used for the preparation ofmost commercial effervescent powders. It should be noted that, althoughthese methods are intended for the preparation of granules, theformulations of effervescent salts of the present invention could alsobe prepared as tablets, according to known technology for tabletpreparation.

Powder for Suspension

In some embodiments, compositions are provided comprising apharmaceutical at least one proton pump inhibitor, about 5 mEq to about11 mEq of an antacid, and at least one suspending agent for oraladministration to a subject. The composition may be a powder forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained. See U.S. patent application Ser. No. 10/893,092,filed Jul. 16, 2004, which claims priority to U.S. ProvisionalApplication No. 60/488,324 filed Jul. 18, 2003, both of which are hereinincorporated by reference in their entirety.

A suspension is “substantially uniform” when it is mostly homogenous,that is, when the suspension is composed of approximately the sameconcentration of proton pump inhibitor at any point throughout thesuspension. A suspension is determined to be composed of approximatelythe same concentration of proton pump inhibitor throughout thesuspension when there is less than about 20%, less than about 15%, lessthan about 13%, less than about 11%, less than about 10%, less thanabout 8%, less than about 5%, or less than about 3% variation inconcentration among samples taken from various points in the suspension.

The concentration at various points throughout the suspension can bedetermined by any suitable means known in the art. For example, onesuitable method of determining concentration at various points involvesdividing the suspension into three substantially equal sections: top,middle and bottom. The layers are divided starting at the top of thesuspension and ending at the bottom of the suspension. Any number ofsections suitable for determining the uniformity of the suspension canbe used, such as for example, two sections, three sections, foursections, five sections, or six or more sections.

In one embodiment, the composition comprises at least one proton pumpinhibitor, between about 5 mEq to about 11 mEq of antacid, and a gumsuspending agent, wherein the average particle size of the insolublematerial is less than about 200 μm. In some embodiments, the averageparticle size of the insoluble material is less than about 100 μm. Inother embodiments, the average particle size of the insoluble materialis less than about 50 μm. The composition is a powder for suspension,and upon admixture with water, a first suspension is obtained that issubstantially more uniform when compared to a second suspensioncomprising the proton pump inhibitor, the antacid, and suspending agent,wherein the suspending agent is not xanthan gum.

In another embodiment, the composition comprises omeprazole, sodiumbicarbonate and xanthan gum. The composition is a powder for suspension,and upon admixture with water, a substantially uniform suspension isobtained. In yet another embodiment, the composition is a powder forsuspension and comprises omeprazole, about 5 mEq to about 11 mEq sodiumbicarbonate, xanthan gum, and at least one sweetener or flavoring agent.

Combination Therapy

The compositions and methods described herein may also be used inconjunction with other well known therapeutic reagents that are selectedfor their particular usefulness against the condition that is beingtreated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical composition, and may,because of different physical and chemical characteristics, have to beadministered by different routes. The determination of the mode ofadministration and the advisability of administration, where possible,in the same pharmaceutical composition, is well within the knowledge ofthe skilled clinician. The initial administration can be made accordingto established protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the proliferative disease, the condition ofthe patient, and the actual choice of compounds used. The determinationof the order of administration, and the number of repetitions ofadministration of each therapeutic agent during a treatment protocol, iswell within the knowledge of the skilled physician after evaluation ofthe disease being treated and the condition of the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include the typeof gastric acid disorder from which the subject suffers, the proton pumpinhibitor being administered, as well as the age, weight, sex, diet, andmedical condition of the subject. Thus, the dosage regimen actuallyemployed can vary widely and therefore can deviate from the dosageregimens set forth herein. For example, proton pump inhibitors can beformulated to deliver rapid relief as well as sustained relief of agastric acid related disorder.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In some embodiments, the present methods, kits, and compositions can beused in combination with another pharmaceutical agent that is indicatedfor treating or preventing a gastrointestinal disorder, such as, forexample, an anti-bacterial agent, an alginate, a prokinetic agent, or anH₂-antagonist which are commonly administered to minimize the painand/or complications related to this disorder. These drugs have certaindisadvantages associated with their use. Some of these drugs are notcompletely effective in the treatment of the aforementioned conditionsand/or produce adverse side effects, such as mental confusion,constipation, diarrhea, and thrombocytopenia.

In other embodiments, the present methods, kits, and compositions can beused in combination with other pharmaceutical agents, including but notlimited to: NSAIDs including but not limited to aminoarylcarboxylic acidderivatives such as enfenamic acid, etofenamate, flufenamic acid,isonixin, meclofenamic acid, mefenamic acid, niflumic acid,talniflumate, terofenamate, and tolfenamic acid; arylacetic acidderivatives such as aceclofenac, acemetacin, alclofenac, amfenac,amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac,diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac,glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac,metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin,sulindac, tiaramide, tolmetin, tropesin, and zomepirac; arylbutyric acidderivatives such as bumadizon, butibufen, fenbufen, xenbucin;arylcarboxylic acids such as clidanac, ketorolac, tinoridine;arylpropionic acid derivatives such as alminoprofen, benoxaprofin,bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen,naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinicacid, suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen; pyrazolessuch as difenamizole, and epirozole; pyrazolones such as apazone,benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone,phenylbutazone, pipebuzone, propyphenazone, prostaglandins,ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acidderivatives such as acetaminosalol, aspirin, benorylate, bromosaligenin,calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisicacid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate,mesalamine, morpholine salicylate, 1-naphtyl salicylate, olsalazine,parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide,salicylamide o-acetic acid, salicylsulfinuric acid, salsalate,sulfasalazine; thiazinecarboxamides such as ampiroxicam, droxicam,isoxicam, lomoxicam, piroxicam, and tenoxicam; cyclooxygenase-IIinhibitors (“COX-II”) such as Celebrex (Celecoxib), Vioxx, Relafen,Lodine, and Voltaren and others, such as epsilon-acetamidocaproic acid,s-adenosylmethionine, 3-amino-4-hydroxybutytic acid, amixetrine,bendazac, benzydamine, α-bisabolol, bucololome, difenpiramide, ditazol,emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol,paranyline, perisoxal, proquazone, tenidap and zilenton; sleep aidsincluding but not limited to a benzodiazepine hypnotic,non-benzodiazepine hypnotic, antihistamine hypnotic, antidepressanthypnotic, herbal extract, barbiturate, peptide hypnotic, triazolam,brotizolam, loprazolam, lormetazepam, flunitrazepam, flurazepam,nitrazepam, quazepam, estazolam, temazepam, lorazepam, oxazepam,diazepam, halazepam, prazepam, alprazolam, chlordiazepoxide,clorazepate, an imidazopyridine or pyrazolopyrimidine hypnotic, zolpidemor zolpidem tartarate, zopiclone, eszopiclone, zaleplon, indiplone,diphenhydramine, doxylamine, phenyltoloxamine, pyrilamine, doxepin,amtriptyline, trimipramine, trazodon, nefazodone, buproprion,bupramityiptyline, an herbal extract such as valerian extract oramentoflavone, a hormone such as melatonin, or gabapeptin; motilityagents, including but not limited to 5-HT inhibitors such as cisapride,domperidone, and metoclopramide, and agents useful for treatingirritable bowel syndrome.

For the sake of brevity, all patents and other references cited hereinare incorporated by reference in their entirety.

EXAMPLES

The present invention is further illustrated by the following examples,which should not be construed as limiting in any way. The experimentalprocedures to generate the data shown are discussed in more detailbelow. For all formulations herein, multiple doses may be proportionallycompounded as is known in the art. The coatings, layers andencapsulations are applied in conventional ways using equipmentcustomary for these purposes.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology used is intended to be in the natureof description rather than of limitation.

Example 1 Modified Fuchs Model for Antacid Selection

Samples were prepared and analyzed using a method that is a variation ofthe Fuchs' procedure described in the literature. The proceduredescribed simulates a gastric environment with continuous acid influx. Adescription of experimental set-up and sample analysis is providedbelow. Changes may be made to these instructions after initial sampleevaluation to optimize sample analysis and collection of relevantinformation.

Set-Up:

-   -   1. A glass sample vessel (˜150 mL capacity) containing 50 mL of        a standardized solution of 0.1 N HCl was placed into a water        bath set at 37° C. (±2° C.).    -   2. A second glass vessel containing >70 mL of a standardized        solution of 1.0 N HCl was placed into the same water bath.    -   3. The stir paddle was then placed into the sample vessel and        set at an appropriate speed. The speed of the stir paddle was        recorded and used for all samples analyzed. The speed of the        paddle should be adequate to dissolve the sample and added acid        without causing interference with the pH measurement or        splashing of the solution.    -   4. Prior to the start of each sample analysis, the tubing was        primed and it was verified that the flow rate with 1.0 N HCl was        0.5 mL/min and the temperature was 37° C. (+2° C.). The pump and        tubing were then set-up to allow the transfer of 1.0 N HCl acid        into the sample vessel.    -   5. The pH meter was calibrated to accurately measure pH between        1 and 10 and it was verified that the electronic storage device        was ready to collect pH and/or temperature data at a pre-defined        rate.    -   6. When necessary, the sample was crushed into a fine powder        using a mortar and pestle and then transferred to a suitable        container and weighed.    -   7. The pH probe was placed into the glass sample vessel        containing 50 mL of 0.1 N HCl at 37° C. (±2° C.).    -   8. The timer and pH data collection was then started. The sample        was then transferred into the vessel and the exact time that the        sample was introduced into the acid was recorded. The sample        container was then re-weighed to determine the exact weight        added.    -   9. The sample was then stirred for approximately 6 minutes and        the flow of the 1.0 N HCl at a rate of 0.5 mL/min was started.        The exact start time of the acid flow was recorded.    -   10. For samples with not more than (≦) 30 mEq ANC the sample        continued to stir and the pH was monitored for 1 hour in 15        second intervals.    -   11. The duration of the test was recorded and the total volume        of 0.1 N HCl added was calculated based on the flow rate.

Various buffer combinations were screened using this modified Fuchsin-vitro dynamic stomach model, described above, and it was discoveredthat the correlation of the theoretical ANC of a given buffer to theactual neutralization capacity and the speed depended on several factorssuch as solubility, particle size, presence and level of binders and/ordisintegrants. For example, it was determined that the smaller theparticle size of the buffer the closer the theoretical value was to theactual ANC of a given buffer. This particle size effect was especiallynoticeable for the insoluble or sparingly soluble antacids such ascalcium carbonate or magnesium hydroxide. Contrastingly, the larger theparticles size of the antacids, the lower the actual ANC was (e.g.,sub-100 US mesh size, sub-80 US mesh size, and sub-60 mesh size ofMagnesium Hydroxide).

It was also determined that spray dried magnesium hydroxide with 5%starch such as MS-90@ from SPI Pharma performed better than the USPgrade manufactured by precipitation (USP grade Magnesium Hydroxide) inthe on set speed of neutralization. In similar pattern, It spray driedcalcium carbonate with 5% starch such as Destab® Calcium carbonate-95Sfrom Particle Dynamics performed better than the USP grade calciumcarbonate manufactured by precipitation in the on set speed ofneutralization as well as the actual neutralization capacity measured bythe area under curve (AUC) of the dynamic pH profile.

Example 2 Disintegrant Optimization Trials: Mixed Buffer System

Most proton pump inhibitors are sparingly soluble in water. Thesesparingly soluble drugs have a strong correlation of disintegration timeto bioavailability, and it is important to optimize the disintegrationtime, which enhances in vivo dissolution of the drug. This trial used asub-80 mesh US mesh size magnesium hydroxide based formulation as shownin Table 2.A.1 and tested levels between 3% and 11% levels ofdisintegrant (Croscarmellose Sodium, Ac-di-Sol) for the capsule dosageform performance. Disintegration test outlined by USP (United StatePharmacopia) was chosen as the test method to determine the optimallevel of disintegrant. All capsule products containing between 5% to 11%Ac-Di-Sol performed similarly in terms of their physical characteristic,flow properties, and encapsulation characteristics. Disintegrationtesting of samples with mixed buffer systems indicated that capsuledisintegration time is reduced when the level of disintegrant isincreased from 3% to 5%. Increasing the level of disintegrant beyond 5%did not lower the disintegration time significantly.

Capsules were filled on a Pharm Op Zansi® LZ-64 dosator encapsulatorusing the compositions set forth in Table 2.A.1, below. The results ofthe disintegration study are shown in Table 2.A.2, below.

TABLE 2.A.1 Disintegrant Optimization Trials SAN-10D1 SAN-10D2 SAN-10D3SAN-10D4 3% 5% 8% 11% Disintegrant Disintegrant DisintegrantDisintegrant Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % OMEPRAZOLEUSP 40.8 4.1 40.8 4.1 40.8 3.9 40.8 3.8 Sodium Bicarbonate #2 USP 42043.4 420 42.6 420 41.2 420 39.9 Magnesium Hydroxide 470 48.6 470 47.7470 46.2 470 44.6 (sieved) sub 80 mesh Croscarmellose Sodium NF 30 3.149 5.0 81 8.0 116 11.0 Magnesium Stearate NF 7 0.7 7 0.7 7 0.7 7 0.7Totals: 967 100.0 986 100.0 1018 100.0 1053 100.0

TABLE 2.A.2 Disintegrant Optimization Trials Disintegration TrialNumber/ Times Description First Last Comments/Observations SAN-10D1 (3%Ac-Di-Sol) 9′10″ 11′20″ Virtually all disintegrated at 9 mins. SAN-10D2(5% Ac-Di-Sol) 7′30″ 12′ Virtually all disintegrated at 7 mins 30 secs.SAN-10D3 (8% Ac-Di-Sol) 8′ 11′ Virtually all disintegrated at 7 mins.SAN-10D4 (11% Ac-Di-Sol) 7′30″ 10′30″ Virtually all disintegrated at 7mins.

Example 2B Disintegrant Optimization Trials—Sodium Bicarbonate Buffer

Sodium bicarbonate has effervescent characteristic when mixed with acidsuch as gastric fluid. This facilitates the disintegration time of acapsule product, and the disintegration requirement would be less thanthat of the mixed buffer system when sodium bicarbonate is used as asingle buffer. This trial used a USP#2 grade sodium bicarbonate basedformulation as shown in table 2.B.1. and tested levels between 1% and 5%levels of disintegrant (Croscarmerllose Sodium, Ac-di-Sol) for thecapsule dosage form performance. Disintegration test outlined by USP(United State Pharmacopia) was chosen as the test method to determinethe optimal level of disintegrant. All capsule products containingbetween 1% to 5% Ac-Di-Sol performed similarly in terms of theirphysical characteristic, flow properties, and encapsulationcharacteristics. However, disintegration testing of samples indicatedthat capsule disintegration time is reduced when the level ofdisintegrant is increased from 1% to 2%. Increasing the level ofdisintegrant beyond 3% did not lower the disintegration timesignificantly.

TABLE 2.B.1 Disintegrant Optimization Trials SAN-10BB1 SAN-10BB2SAN-10BB3 SAN-10BB4 1% 2% 3% 5% Disintegrant Disintegrant DisintegrantDisintegrant Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % OMEPRAZOLEUSP 40 3.5 40 3.4 40 3.4 40 3.3 Sodium Bicarbonate #2 USP 1100 94.9 110094.0 1100 93.1 1100 91.1 Croscarmellose Sodium NF 12 1.0 23 20. 35 3.060 5.0 Magnesium Stearate NF 7 0.6 7 0.6 7 0.6 7 0.6 Totals: 967 100.0986 100.0 1018 100.0 1053 100.0

TABLE 2.B.2 Disintegrant Optimization Trials: Sodium Bicarbonate BufferDisintegration Trial Number/ Times Description First LastComments/Observations SAN-10BB1 (1% Ac-Di-Sol) 6′40″ 8′20″ Virtually alldisintegrated at 7 mins. SAN-10BB2 (2% Ac-Di-Sol) 4′30″ 6′ Virtually alldisintegrated at 5 mins 30 secs. SAN-10BB3 (3% Ac-Di-Sol) 4′ 5′30″Virtually all disintegrated at 5 mins. SAN-10BB4 (5% Ac-Di-Sol) 4′ 5′30″Virtually all disintegrated at 5 mins.

Example 3 Binder Optimization Trials

A low level of binder 3-8% is commonly used in capsule productmanufacturing to make a plug before encapsulation. The use of the bindersuch as Klucel®-EXP (hydroxypropyl cellulose) or microcrystallinecellulose (Avicel® PH-102, PH-200) was evaluated with the presence of0-5% of disintegrant in the powder for the performance using the dynamicstomach model (modified Fuchs model). In general use of the binder had anegative impact on the actual ANC and the speed of neutralization in thepH profiling tests, unless used in combination with a disintegrant.

TABLE 3.A.1 Binder Optimization Trials SAN-10F1 SAN-10F2 SAN-10F3SAN-10F4 SAN-10F5 Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % Mg/cap% Omeprazole USP 40.0 4.5 40.0 4.0 40.0 3.8 40.0 3.6 40.0 3.6 SodiumBicarbonate #2 250 27.9 250 25.1 350 33.4 350 31.9 350 31.9 USPMagnesium Hydroxide 600.0 66.9 600.0 60.2 600.0 57.3 600.0 54.7 600.054.7 Klucel-EXP 0 0.0 100 10.0 50 4.8 100 9.1 50 4.6 CroscarmelloseSodium 0 0.0 0 0.0 0 0.0 0 0.0 50 4.6 NF Magnesium Stearate 7 0.8 7 0.77 0.7 7 0.6 7 0.6 NF Totals: 897.0 100.0 997.0 100.0 997.0 100.0 1,097.0100.0 1,097.0 100.0

TABLE 3.A.2 Binder Optimization Trials TR2001 TR2002 TR2003 TR2004TR2005 Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % Mg/cap %Omeprazole USP 40 4.5 40 4.0 40 4.0 40 3.6 40 3.6 Sodium 450 50.2 45045.1 450 45.1 450 41.0 450 41.0 Bicarbonate #2 USP Magnesium 500 55.7500 50.2 500 50.2 500 45.6 500 45.6 Hydroxide Klucel-EXP 20 2.2 20 2.050 5.0 50 4.6 0 0.0 Croscarmellose Sodium NF 20 2.2 50 5.0 50 5.0 20 1.820 1.8 Magnesium 7 0.8 7 0.7 7 0.7 7 0.6 7 0.6 Stearate NF Totals: 897100.0 997 100.0 997 100.0 1,097.0 100.0 1,097.0 100.0

The pH test results (table 3.A.1. and table 3.A.2.) shows thathand-filled capsules with the binders at 5-10% level had a very slowneutralization speed while the capsule with binder and disintegrant hadan adequate speed of neutralization. The capsules with no binder and nodisintegrant showed a medium neutralization speed. Table 3BB showed thesimilar findings that the presence of binder slows down theneutralization speed while use of disintegrant mitigate the negativeimpact of binder in the formulation.

TABLE 3.B.1 Neutralization Speed of Capsules with Various Level ofBinder and Disintegrant Binder Total Total Time Above pH LevelDisintegrant ANC (min) Sample (%) Level (%) (mEq) 3.5 5.0 6.0 6.5SAN-10F1 0 0 23.6 14.75 11.25 5.75 1.50 SAN-10F2 10 0 23.6 0 0 0 0SAN-10F3 0 4.8 24.7 19.5 18.25 12.2 6.50 SAN-10F4 9.1 4.8 24.7 15.4511.30 9.50 7.45 SAN-10F5 4.6 4.6 24.7 34.25 30.00 22.50 15.25

TABLE 3.B.2 Neutralization Speed of Capsules with Various Level ofBinder and Disintegrant Binder Total Level Disintegrant ANC Total TimeAbove pH (min) Sample (%) Level (%) (mEq) 3.5 5.0 6.0 6.5 TR2001 2.2 2.222.5 8.5 7.00 0.25 0 TR2002 2.0 5.0 22.5 0.25 0 0 0 TR2003 5.0 5.0 22.57.25 6.00 0.25 0 TR2004 4.6 1.8 22.5 0 0 0 0 TR2005 0.0 1.8 22.5 0 0 0 0

Example 4 Capsule Formulations

The following formulations were prepared by the following process: Thesodium bicarbonate and omeprazole were combined in a mixer and blendedfor 5 minutes. To that mixture, the magnesium hydroxide (if any) andcroscarmellose sodium were added and mixed for 5 minutes. The blend wasthen passed through a #20 mesh s/s screen and then mixed for 10 minutes.Magnesium stearate was then added to the mixture and blended for 3minutes. The material was then encapsulated into hard gelatin capsuleshells using a Profill® manual capsule filler.

SAN-10A SAN-10B SAN-10BB SAN-10C Ingredients Mg/caps Mg/caps Mg/capsMg/caps OMEPRAZOLE USP 40 40 40 20 Sodium Bicarbonate 420 420 1100 800#2 USP Magnesium Hydroxide 470 0 0 0 (sieved) 100 mesh MagnesiumHydroxide 0 470 0 0 (sieved) 60 mesh Croscarmellose 30 30 20 20 SodiumNF Magnesium 10 10 10 8 Stearate NF Totals: 970 970 1170 848

SAN-10D SAN-10E SAN-10F SAN-10G SAN-10H Ingredients Mg/caps Mg/capsMg/caps Mg/caps Mg/caps OMEPRAZOLE USP 40 40 40 40 40 Sodium Bicarbonate#2 420 378 335 378 420 USP Magnesium Hydroxide 470 0 0 0 0 (sieved) 80mesh Magnesium Hydroxide 0 0 375 0 375 (sieved) 60 mesh MagnesiumHydroxide 95- 0 447.4 0 447.4 0 MS Croscarmellose Sodium NF 30 27 24 5682 Magnesium Stearate NF 7 6 5 6 5 Totals: 967 898.4 779.8 928 922

Example 5 Capsule Formulations with Sodium Bicarbonate and Less than 3%Disintegrant

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI as well assufficient buffering agent to prevent acid degradation of at least someof the PPI by raising the pH of gastric fluid. Amounts of buffer areexpressed in weight as well as in molar equivalents (mEq). The capsulesare prepared by blending the PPI with one or more buffering agents, andhomogeneously blending with excipients. The appropriate weight of bulkblend composition is filled into a hard gelatine capsule (e.g., size 00)using an automatic encapsulator. The PPI can be in a micronized form.

PPI Buffering Agent Excipient 40 mg omeprazole 11.3 mEq or 950 mg NaHCO₃50 mg Klucel 30 mg Ac-di-Sol 10 mg magnesium stearate 2.8% disintegrant

PPI Buffering Agent Excipient 40 mg omeprazole 10.5 mEq or 880 mg 30 mgKlucel NaHCO₃ 20 mg Crospovidone 10 mg magnesium stearate 2.0%disintegrant

PPI Buffering Agent Excipient 60 mg omeprazole per 11.4 mEq or 960 mg 20mg MCC capsule NaHCO₃ 25 mg Ac-Di-Sol 10 mg magnesium stearate 1.9%disintegrant

Example 6 Capsule Formulations with Mixed Buffer Systems and 3-11%Disintegrant

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI as well assufficient buffering agent to prevent acid degradation of at least someof the PPI by raising the pH of gastric fluid. Amounts of buffer areexpressed in weight as well as in molar equivalents (mEq). The capsulesare prepared by blending the PPI with one or more buffering agents, andhomogeneously blending with excipients. The appropriate weight of bulkblend composition is filled into a hard gelatinecapsule (e.g., size 00)using an automatic encapsulator. The PPI can be in a micronized form.

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 20 mg MCComeprazole   3 mEq or 250 mg NaHCO₃ 50 mg Ac-di-Sol 23.6 mEq or 950 mgstotal 10 mg magnesium buffer stearate 5.2% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 100 mgMCC omeprazole   3 mEq or 250 mg NaHCO₃  50 mg Ac-di-Sol 23.6 mEq or 950mgs total  10 mg magnesium buffer stearate 4.8% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂  30 mgMCC omeprazole   3 mEq or 250 mg NaHCO₃ 100 mg sodium starch 23.6 mEq or950 mgs total glycolate (Primojel ®) buffer  10 mg magnesium stearate9.7% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 50 mgKlucel omeprazole   3 mEq or 250 mg NaHCO₃ 50 mg Ac-di-Sol 23.6 mEq or850 mgs total 10 mg magnesium buffer stearate 5.0% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 30 mgKlucel omeprazole   3 mEq or 250 mg NaHCO₃ 30 mg Ac-di-Sol 23.6 mEq or850 mgs total 10 mg magnesium buffer stearate 3.1% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 100 mgKlucel omeprazole   3 mEq or 250 mg NaHCO₃  30 mg Ac-di-Sol 23.6 mEq or850 mgs total  10 mg magnesium buffer stearate 3.0% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 30 mgKlucel omeprazole  3.0 mEq or 250 mg NaHCO₃ 70 mg Crospovidone 23.6 mEqor 850 mgs total 10 mg magnesium buffer stearate 7.1% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 50 mgAc-Di-Sol omeprazole  3.0 mEq or 250 mg NaHCO₃ 30 mg Klucel per capsule23.6 mEq or 850 mgs total 10 mg magnesium buffer stearate 5.2%disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 40 mgAc-Di-Sol omeprazole per  4.2 mEq or 350 mg NaHCO₃ 35 mg Klucel capsule24.7 mEq or 950 mg total 10 mg magnesium buffer stearate 4.1%disintegrant

PPI Buffering Agent Excipient 15 mg  17.1 mEq or 500 mg Mg(OH)₂ 50 mgAc-Di-Sol microencapsulated  3.0 mEq or 250 mg NaHCO₃ 15 mg Klucellansoprazole per 20.71 mEq or 750 mg total  7 mg capsule buffermagnesium stearate 6.0% disintegrant

PPI Buffering Agent Excipient 30 mg 17.1 mEq or 500 mg Mg(OH)₂ 40 mgAc-Di-Sol lansoprazole per  4.2 mEq or 350 mg NaHCO₃ 30 mg Klucelcapsule 21.3 mEq or 850 mg total 10 mg magnesium buffer stearate 4.2%disintegrant

PPI Buffering Agent Excipient 60 mg 17.1 mEq or 500 mg 30 mgCrospovidone ompeprazole Mg(OH)₂ per capsule  3.0 mEq or 250 mg NaHCO₃15 mg Klucel 20.1 mEq or 750 mg total  7 mg magnesium stearate buffer3.5% disintegrant

PPI Buffering Agent Excipient 10 mg 17.1 mEq or 500 mg 30 mg sodiumstarch ompeprazole Mg(OH)₂ glycolate (Explotab ®) per capsule  3.0 mEqor 250 mg NaHCO₃ 15 mg Klucel 20.1 mEq or 750 mg total  7 mg magnesiumstearate buffer 3.7% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 50 mgAc-Di-Sol microencapsulated  3.0 mEq or 250 mg NaHCO₃ 50 mg Klucelomeprazole 23.6 mEq or 850 mg total 10 mg per capsule buffer magnesiumstearate 5.1% disintegrant

PPI Buffering Agent Excipient 40 mg 17.1 mEq or 500 mg Mg(OH)₂ 40 mgAc-Di-Sol omeprazole per  4.2 mEq or 350 mg NaHCO₃ 45 mg Klucel capsule21.3 mEq or 850 mg total 10 mg magnesium buffer stearate 4.1%disintegrant

PPI Buffering Agent Excipient 15 mg 17.1 mEq or 500 mg 30 mgCrospovidone lansoprazole per Mg(OH)₂ 15 mg Klucel capsule  3.0 mEq or250 mg NaHCO₃  7 mg magnesium 20.1 mEq or 750 mg total stearate buffer3.7% disintegrant

PPI Buffering Agent Excipient 20 mg 17.1 mEq or 500 mg Mg(OH)₂ 50 mgAc-Di-Sol omeprazole per  3.0 mEq or 250 mg NaHCO₃ 30 mg Klucel capsule20.1 mEq or 750 mg total 10 mg magnesium buffer stearate 5.8%disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 40 mgAc-Di-Sol omeprazole  4.2 mEq or 350 mg NaHCO₃ 35 mg Klucel per capsule24.8 mEq or 950 mg total 10 mg magnesium buffer stearate 3.7%disintegrant

PPI Buffering Agent Excipient 15 mg 17.1 mEq or 500 mg Mg(OH)₂ 60 mgAc-Di-Sol microencapsulated  3.0 mEq or 250 mg NaHCO₃ 15 mg Klucellansoprazole 20.1 mEq or 750 mg total  7 mg per capsule buffer magnesiumstearate 7.1% disintegrant

PPI Buffering Agent Excipient 60 mg 17.1 mEq or 500 mg Mg(OH)₂ 30 mgAc-Di-Sol ompeprazole per  3.0 mEq or 250 mg NaHCO₃ 15 mg Klucel capsule20.1 mEq or 750 mg total  7 mg magnesium buffer stearate 3.5%disintegrant

PPI Buffering Agent Excipient 20 mg  6.9 mEq or 200 mg Mg(OH)₂ 30 mgAc-Di-Sol omeprazole per  3.9 mEq or 330 mg NaHCO₃ 35 mg Klucel capsule10.8 mEq or 530 mg total  6 mg magnesium Size 0 capsule buffer stearate4.8% disintegrant

PPI Buffering Agent Excipient 15 mg 6.9 mEq or 200 mg Mg(OH)₂ 35 mgAc-Di-Sol micro- 2.6 mEq or 220 mg NaHCO₃ 20 mg Klucel encapsulated 8.5mEq or 420 mg total buffer  6 mg magnesium lansoprazole stearate percapsule 7.1% disintegrant Size 1 capsule

PPI Buffering Agent Excipient 30 mg 3.4 mEq or 100 mg Mg(OH)₂ 20 mgAc-Di-Sol lansoprazole 3.8 mEq or 315 mg NaHCO₃ 30 mg Klucel per capsule7.2 mEq or 415 mg total  5 mg magnesium Size 1 capsule buffer stearate4.0% disintegrant

PPI Buffering Agent Excipient 60 mg 5.1 mEq or 150 mg Mg(OH)₂ 20 mgAc-Di-Sol ompeprazole 3.0 mEq or 250 mg NaHCO₃ 10 mg Klucel per capsule8.1 mEq or 400 mg total  4 mg magnesium Size 2 capsule buffer stearate4.1% disintegrant

PPI Buffering Agent Excipient 120 mg  8.6 mEq or 250 mg Mg(OH)₂ 30 mgAc-Di-Sol ompeprazole  2.4 mEq or 200 mg NaHCO₃ 30 mg Klucel per capsule11.0 mEq or 450 mg total buffer  8 mg magnesium Size 1 capsule stearate4.7% disintegrant

PPI Buffering Agent Excipient 10 mg 3.4 mEq or 100 mg Mg(OH)₂ 18 mgAc-Di-Sol ompeprazole 3.0 mEq or 250 mg NaHCO₃ 15 mg Klucel per capsule6.4 mEq or 350 mg total buffer  7 mg magnesium Size 2 capsule stearate4.5% disintegrant

Example 7A Capsule Formulations without Binder

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI as well assufficient buffering agent to prevent acid degradation of at least someof the PPI by raising the pH of gastric fluid. Amounts of buffer areexpressed in weight as well as in molar equivalents (mEq). The capsulesare prepared by blending the PPI with one or more buffering agents, andhomogeneously blending with excipients. The appropriate weight of bulkblend composition is filled into a hard gelatine capsule (e.g., size 00)using an automatic encapsualtor. The PPI can be in a micronized form.

TABLE 7A PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂50 mg Ac-di-Sol omeprazole  3.0 mEq or 250 mg NaHCO₃ 10 mg magnesium23.6 mEq or 950 mgs total buffer stearate

TABLE 7B PPI Buffering Agent Excipient 40 mg 15.4 mEq or 450 mg Mg(OH)₂30 mg Ac-Di-Sol microencapsulated  2.4 mEq or 200 mg NaHCO₃  7 mgompeprazole per 17.8 mEq or 650 mg total magnesium capsule bufferstearate

TABLE 7C PPI Buffering Agent Excipient 40 mg 10.5 mEq or 880 mg NaHCO₃20 mg Ac-Di-Sol omeprazole 10.5 mEq or 880 mg total  9 mg magnesiumstearate per capsule buffer Size 0 Elongated capsule

TABLE 7D PPI Buffering Agent Excipient 40 mg 3.4 mEq or 100 mg Mg(OH)₂20 mg Ac-Di-Sol microencapsulated 2.4 mEq or 200 mg NaHCO₃  5 mgmagnesium ompeprazole 5.8 mEq or 300 mg total stearate per capsulebuffer Size 2 capsule

Example 7B 40 mg Omeprazole (SAN-7E)

The following specific formulations are provided by way of illustratingthe present invention and are not intended to be limiting. The capsuleswere prepared by blending the indicated amount of micronized omeprazoleUSP (purchased from Union Quimico Farmaceutica, “UQUIFA”) about half theindicated amount of sodium bicarbonate USP #2. After blending theomeprazole and sodium bicarbonate, the remaining sodium bicarbonate USP#2 was added along with the indicated amount of croscarmellose sodiumand magnesium stearate. Once the omeprazole was homogeneously blendedwith the excipients, the appropriate weight of composition was filledinto hard gelatin capsules, size 00, using a dosing disc/tamplingpin-type automatic encapsulator.

In particular, a 110 kg blend for manufacturing 40 mg/capsule omeprazoleimmediate release capsules according to the present invention wasmanufactured by the following procedure: First, about half of the sodiumbicarbonate was blended with omeprazole in a 5 cubic foot V-blender.First, about one quarter of the total sodium bicarbonate (i.e. about 25%of 102.47 kg (the total amount of sodium bicarbonate USP #2) was passedthrough a 16/20 mesh screen and charged into the V-blender. Next, 3.80kg of omeprazole USP were passed through a 16/20 mesh screen and chargedinto the V-blender. Then, about one quarter of the total sodiumbicarbonate were passed through the 16/20 mesh screen and charged intothe V-blender. Once the sodium bicarbonate (about half the total) andomeprazole were charged into the V-blender, they were mixed for 5minutes to form a pre-blend.

Next, about half of the sodium bicarbonate and the crocarmellose wasadded to the pre-blend. Approximately one quarter of the of the totalsodium bicarbonate was passed through a 16/20 mesh screen and chargedinto the V-blender. Then 2.79 kg of crocarmellose sodium NF, EP waspassed through the 16/20 mesh screen and charged into the V-blender.Finally, the remaining one quarter of the sodium bicarbonate was passedthrough the screen and charged into the V-blender. The resulting mixturewas 5 minutes, sampled for BU, mixed again for 5 minutes, sampled forBU, mixed again for 5 minutes, and sampled again for BU.

Last, magnesium stearate was added to the mixture. The magnesiumstearate, 0.93 Kg, was passed through a 30 mesh screen and charged intothe V-blender. The mixture was mixed for 3 minutes then discharged intoa drum. The mixture was then sampled for BU and then encapsulated insize 00 hard gelatin capsules on a H&K tamping pin encapsulator.

The amounts of omeprazole and excipients used in this example are setforth in the following table:

TABLE 7E Amount Acid Neutralizing Required Content Ingredient %mg/capsule for 110 Kg: (meq per capsule) Omeprazole USP 3.5% 40.8*mg/caps 3.80 Kg — Sodium Bicarbonate USP #2 93.2 1100 102.47 13.1 meqCroscarmellose Sodium NF, EP 2.5 30 2.79 — Magnesium Stearate 0.8 100.93 — Total: 100.0 1180.8 110.00 13.1 *An overage of 2% of omeprazolewas used to ensure at least 100% indicated omeprazole per capsule.

Example 7C 20 mg Omeprazole (SAN-7F)

In another particular example, a 1300 Kg blend of 20 mg omeprazole percapsule was manufactured by the following procedure:

First, about half of the sodium bicarbonate was blended with omeprazolein a 60 cubic foot V-blender. About one quarter of the total sodiumbicarbonate (i.e. about 25% of 1232.33 kg (the total amount of sodiumbicarbonate USP #2) was passed through a 16/20 mesh screen and chargedinto the V-blender. Next, 22.85 Kg of omeprazole USP were passed throughthe 16/20 mesh screen and charged into the V-blender. Then, about onequarter of the total sodium bicarbonate were passed through the 16/20mesh screen and charged into the V-blender. Once the sodium bicarbonate(about half the total) and omeprazole were charged into the V-blender,they were mixed for 5 minutes to form a pre-blend.

Next, about half of the sodium bicarbonate and the croscarmellose wasadded to the pre-blend. Approximately one quarter of the of the totalsodium bicarbonate was passed through a 16/20 mesh screen and chargedinto the V-blender. Then 33.61 Kg of Croscarmellose sodium NF, EP waspassed through the 16/20 mesh screen and charged into the V-blender.Finally, the remaining one quarter of the sodium bicarbonate was passedthrough the screen and charged into the V-blender. The resulting mixturewas mixed 5 minutes, sampled for batch uniformity (BU), mixed again for5 minutes, sampled for BU, mixed again for 5 minutes, and sampled againfor BU.

Last, magnesium stearate was added to the mixture. The magnesiumstearate, 11.20 Kg, was passed through a 30 mesh screen and charged intothe V-blender. The mixture was mixed for 3 minutes then discharged intoa drum. The mixture was then sampled for BU and encapsulated in size 00hard gelatin capsules on a H&K tamping pin encapsulator.

The amounts of omeprazole and excipients used in this example are setforth in the following table:

TABLE 7F Amount Acid Neutralizing Required Content Ingredient %mg/capsule for 110 Kg: (meq per capsule) Omeprazole USP 1.8% 20.4*mg/capsule 22.85 Kg — Sodium Bicarbonate USP #2 94.8 1100.0 1232.33 13.1meq Croscarmellose Sodium NF, 2.6 30.0 33.61 — EP Magnesium Stearate 0.910.0 11.20 — Total: 100.1 1160.4 1300.00 13.1 *An overage of 2%omeprazole was used to ensure that each capsule contained at least 100%of the indicated dose of 20 mg/capsule.

Example 8 Capsule Formulations

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI as well assufficient antacid to prevent acid degradation of at least some of thePPI by raising the pH of gastric fluid. Amounts of antacid are expressedin weight as well as in molar equivalents (mEq). The capsules areprepared by blending the PPI with antacids, and homogeneously blendingwith excipients as shown in Tables 8.A. to 8.H. below. The appropriateweight of bulk blend composition is filled into a hard gelatine capsule(e.g., size 00) using an automatic encapsualtor (H & K 1500 or MG2 G60).The PPI can be in a micronized form.

TABLE 8.A Omeprazole (20 mg) Capsule PPI Antacid Excipient 20 mg  6.9mEq or 200 mg Mg(OH)₂ 30 mg Ac-Di-Sol omeprazole  3.9 mEq or 330 mgNaHCO₃ 35 mg Klucel per capsule 10.8 mEq or 530 mg total  6 mg magnesiumantacid stearate Size 0 capsule

TABLE 8.B Omeprazole (40 mg) Capsule PPI Antacid Excipient 40 mg 10.5mEq or 880 mg NaHCO₃ 40 mg Ac-Di-Sol omeprazole 10.5 mEq or 880 mg total 9 mg magnesium stearate per capsule antacid Size 0 Elongated capsule

TABLE 8.C Lansoprazole (15 mg) Capsule PPI Antacid Excipient 15 mg 6.9mEq or 200 mg Mg(OH)₂ 35 mg Ac-Di-Sol microencapsulated 2.6 mEq or 220mg NaHCO₃ 20 mg Klucel lansoprazole per 9.5 mEq or 420 mg total  6 mgmagnesium capsule antacid stearate Size 1 capsule

TABLE 8.D Lansoprazole (30 mg) Capsule PPI Antacid Excipient 30 mg 3.4mEq or 100 mg Mg(OH)₂ 20 mg Ac-Di-Sol lansoprazole per 3.8 mEq or 315 mgNaHCO₃ 30 mg Klucel capsule 7.2 mEq or 415 mg total  5 mg magnesiumantacid stearate Size 1 capsule

TABLE 8.E Omeprazole (60 mg) Capsule PPI Antacid Excipient 60 mg 5.1 mEqor 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol omeprazole 3.0 mEq or 250 mg NaHCO₃ 10mg Klucel per capsule 8.1 mEq or 400 mg total  4 mg magnesium stearateantacid Size 2 capsule

TABLE 8.F Omeprazole (60 mg) Capsule PPI Antacid Excipient 120 mg  8.6mEq or 250 mg Mg(OH)₂ 30 mg Ac-Di-Sol omeprazole  2.4 mEq or 200 mgNaHCO₃ 30 mg Klucel per 11.0 mEq or 450 mg total  8 mg magnesium capsuleantacid stearate Size 1 capsule

TABLE 8.G Omeprazole (10 mg) Capsule PPI Antacid Excipient 10 mg 3.4 mEqor 100 mg Mg(OH)₂ 18 mg Ac-Di-Sol microencapsulated 3.0 mEq or 250 mgNaHCO₃ 15 mg omeprazole 6.4 mEq or 350 mg total Microcrystalline) percapsule antacid Cellulose (MCC, PH102 7 mg magnesium stearate Size 2capsule

TABLE 8.H Omeprazole (40 mg) Capsule PPI Antacid Excipient 40 mg 3.4 mEqor 100 mg Mg(OH)₂ 20 mg Ac-Di-Sol microencapsulated 2.4 mEq or 200 mgNaHCO₃  5 mg magnesium omeprazole 5.8 mEq or 300 mg total stearate percapsule antacid Size 2 capsule

Example 9 Tablet Formulations

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI andsufficient antacid to prevent acid degradation of at least some of thePPI by raising the pH of gastric fluid. Amounts of antacid are expressedin weight as well as in molar equivalents (mEq). The tablets areprepared by blending the PPI and antacids, and homogeneously blendingwith excipients as shown in Tables 9.A. to 9.H. below. The appropriateweight of bulk blended composition is compressed using oval shapedtoolings in a rotary press (Manesty Express) to achieve a hardness of15-20 kPa. The PPI can be in a micronized form.

TABLE 9.A Omeprazole (20 mg) Tablet PPI Antacid Excipient 20 mg 5.1 mEqor 150 mg Mg(OH)₂ 30 mg Ac-Di-Sol omeprazole per 4.8 mEq or 400 mgNaHCO₃ 65 mg Klucel tablet 9.9 mEq or 550 mg total 10 mg magnesiumantacid stearate

TABLE 9.B Omeprazole (40 mg) Tablet PPI Antacid Excipient 40 mg 5.1 mEqor 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol microencapsulated 3.0 mEq or 250 mgNaHCO₃ 40 mg omeprazole 8.1 mEq or 350 mg total Microcrystalline pertablet antacid cellulose (MCC, PH102)  7 mg magnesium stearate

TABLE 9.C Lansoprazole (15 mg) Tablet PPI Antacid Excipient 15 mg  8.6mEq or 250 mg Mg(OH)₂ 30 mg Ac-Di-Sol microencapsulated  2.4 mEq or 200mg NaHCO₃ 55 mg Plasdone lansoprazole 11.0 mEq or 450 mg total 8 mgmagnesium per tablet antacid stearate

TABLE 9.D Lansoprazole (30 mg) Tablet PPI Antacid Excipient 30 mg  6.2mEq or 180 mg Mg(OH)₂ 25 mg Ac-Di-Sol lansoprazole  4.2 mEq or 350 mgNaHCO₃ 55 mg Klucel per tablet 10.4 mEq or 430 mg total  8 mg magnesiumantacid stearate

TABLE 9.E Omeprazole (60 mg) Tablet PPI Antacid Excipient 60 mg  7.5 mEqor 220 mg Mg(OH)₂ 20 mg Ac-Di-Sol omeprazole  3.0 mEq or 250 mg NaHCO₃60 mg Klucel per tablet 10.5 mEq or 470 mg total 10 mg magnesium antacidstearate

TABLE 9.F Omeprazole (20 mg) Tablet PPI Antacid Excipient 20 mg 7.5 mEqor 220 mg Mg(OH)₂ 20 mg Ac-Di-Sol omeprazole 2.4 mEq or 200 mg NaHCO₃ 60mg Klucel per tablet 9.9 mEq or 420 mg total  8 mg magnesium stearateantacid

TABLE 9.G Omeprazole (10 mg) Tablet PPI Antacid Excipient 10 mg 3.4 mEqor 100 mg Mg(OH)₂ 15 mg Ac-Di-Sol microencapsulated 3.0 mEq or 250 mgNaHCO₃ 40 mg Klucel omeprazole 6.4 mEq or 350 mg total  6 mg magnesiumper tablet antacid stearate

TABLE 9.H Omeprazole (40 mg) Tablet PPI Antacid Excipient 40 mg 5.1 mEqor 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol micro- 3.8 mEq or 315 mg NaHCO₃ 50 mgMicrocrystalline encapsulated 8.9 mEq or 465 mg total Cellulose (MCC,PH102) omeprazole antacid 10 mg magnesium stearate per tablet

Example 10 Chewable Tablet Formulations

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI andsufficient antacid to prevent acid degradation of at least some of thePPI by raising the pH of gastric fluid. Amounts of antacid are expressedin weight as well as in molar equivalents (mEq). The tablets areprepared by blending the PPI and antacids, and homogeneously blendingwith excipients as shown in Tables 10.A to 10.H. below. The appropriateweight of bulk blended composition is compressed using 17 mm FFBEtoolings in a rotary press (Manesty Express) to achieve a hardness of10-14 kPa. The PPI can be in a micronized form.

TABLE 10.A Omeprazole (20 mg) Chewable Tablet PPI Antacid Excipient 20mg 5.1 mEq or 150 mg Mg(OH)₂ 100 mg Xylitab micro- 3.8 mEq or 315 mgNaHCO₃  30 mg Ac-Di-Sol encapsulated 8.9 mEq or 465 mg total  80 mgKlucel omeprazole antacid  20 mg Sucralose per tablet  10 mg cherryflavor  10 mg magnesium stearate  1 mg Red #40 Lake

TABLE 10.B Omeprazole (40 mg) Chewable Tablet PPI Antacid Excipient 40mg 7.5 mEq or 220 mg Mg(OH)₂ 100 mg Dipac sugar micro- 2.4 mEq or 200 mgNaHCO₃  20 mg Ac-Di-Sol encapsulated 9.9 mEq or 420 mg total  80 mgKlucel omeprazole antacid  17 mg grape flavor per tablet  11 mgmagnesium stearate  1 mg Red #40 Lake  1 mg Blue #2 Lake

TABLE 10.C Lansoprazole (15 mg) Chewable Tablet PPI Antacid Excipient 15mg 5.1 mEq or 150 mg Mg(OH)₂ 80 mg Xylitab lansoprazole 2.4 mEq or 200mg NaHCO₃ 25 mg Ac-Di-Sol per tablet 7.5 mEq or 350 mg total 70 mgMicrocrystalline antacid Cellulose 50 mg Asulfame-K 15 mg grape flavor10 mg magnesium stearate  1 mg red #40 lake  1 mg blue #2 lake

TABLE 10.D Lansoprazole (30 mg) Chewable Tablet PPI Antacid Excipient 30mg 5.1 mEq or 150 mg Mg(OH)₂  70 mg Destab Sugar micro- 3.8 mEq or 315mg NaHCO₃  30 mg Ac-Di-Sol encapsulated 8.9 mEq or 465 mg total 100 mgKlucel lansoprazole antacid  20 mg Asulfame-K per tablet  15 mg cherryflavor  9 mg magnesium stearate  1 mg Red #40 Lake

TABLE 10.E Omeprazole (60 mg) Chewable Tablet PPI Antacid Excipient 60mg 4.4 mEq or 220 mg Ca(OH)₂  80 mg Xylitab micro- 3.6 mEq or 300 mgNaHCO₃  30 mg Ac-Di-Sol encapsulated 8.0 mEq or 520 mg total 100 mgKlucel omeprazole antacid  35 mg Sucralose per tablet  10 mg cherryflavor  9 mg magnesium stearate  2 mg Red #40 Lake

TABLE 10.F Omeprazole (60 mg) Chewable Tablet PPI Antacid Excipient 60mg 3.0 mEq or 150 mg Ca(OH)₂ 70 mg Xylitab omeprazole 3.0 mEq or 250 mgNaHCO₃ 25 mg Ac-Di-Sol per tablet 6.0 mEq or 400 mg total 90 mgMicrocrystalline antacid Cellulose (PH 102)  8 mg mint flavor 10 mgmagnesium stearate

TABLE 10.G Omeprazole (10 mg) Chewable Tablet PPI Antacid Excipient 10mg omeprazole  8.0 mEq or 400 mg Ca(OH)₂ 110 mg Ditab Sugar per tablet 3.6 mEq or 300 mg NaHCO₃  30 mg Ac-Di-Sol 11.6 mEq or 700 mg total  20mg Sucralose antacid 100 mg Klucel  15 mg mint flavor  15 mg magnesiumstearate

TABLE 10.H Omeprazole (40 mg) Chewable Tablet PPI Antacid Excipient 40mg  7.5 mEq or 350 mg Ca(OH)₂ 70 mg Xylitab microencapsulated  3.0 mEqor 250 mg NaHCO₃ 30 mg Ac-Di-Sol omeprazole 10.5 mEq or 600 mg total 10mg Sucralose per tablet antacid 80 mg Klucel 10 mg mint flavor  8 mgmagnesium stearate

Example 11 Bite-Disintegration Chewable Tablet Formulations

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI andsufficient antacid to prevent acid degradation of at least some of thePPI by raising the pH of gastric fluid. Amounts of antacid are expressedin weight as well as in molar equivalents (mEq). The tablets areprepared by blending the PPI with antacids, and homogeneously blendingwith excipients as shown in Tables 11.A to 11.H. below. The appropriateweight of bulk blended composition is compressed using 10 mm FFBEtoolings in a rotary press (Manesty Express) to achieve a hardness of5-9 kPa. The PPI can be in a micronized form.

TABLE 11.A Omeprazole (20 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 20 mg per  7.5 mEq or 350 mg Ca(OH)₂ 20 mg sucralosetablet  3.0 mEq or 250 mg NaHCO₃ 40 mg Ac-Di-Sol 10.5 mEq or 600 mgtotal 30 mg pregelatinized starch antacid 30 mg Klucel 15 mg cherryflavor  8 mg magnesium stearate  1 mg Red #40 Lake

TABLE 11.B Omeprazole (40 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 40 mg  8.0 mEq or 400 mg Ca(OH)₂ 20 mg sucralosemicroencapsulated  3.6 mEq or 300 mg NaHCO₃ 40 mg Ac-Di-Sol omeprazole11.6 mEq or 700 mg total 35 mg per tablet pregelatinized starch 25 mgKlucel 15 mg cherry flavor  8 mg magnesium stearate  1 mg Red #40 Lake

TABLE 11.C Lansoprazole (15 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 15 mg 7.9 mEq or 230 mg Mg(OH)₂ 20 mg sucraloselansoprazole per  3.6 mEq or 300 mg NaHCO₃ 35 mg Ac-Di-Sol tablet 11.5mEq or 530 mg total 35 mg pregelatinized starch 25 mg Klucel 17 mg grapeflavor  8 mg magnesium stearate  1 mg Red #40 Lake  1 mg Blue #2 lake

TABLE 11.D Lansoprazole (30 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 30 mg 5.1 mEq or 150 mg Mg(OH)₂ 27 mg sucralosemicroencapsulated 3.8 mEq or 315 mg NaHCO₃ 40 mg Ac-Di-Sol lansoprazole8.9 mEq or 465 mg total 35 mg per tablet antacid pregelatinized starch30 mg Microcrystalline Cellulose (PH101) 20 mg cherry flavor 10 mgmagnesium stearate  2 mg Red #40 Lake

TABLE 11.E Omeprazole (60 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 60 mg micro-  7.9 mEq or 230 mg Mg(OH)₂ 34 mgsucralose encapsulated  3.0 mEq or 250 mg NaHCO₃ 30 mg Ac-Di-Solomeprazole 10.9 mEq or 480 mg total 35 mg pregelatinized per tabletantacid starch 30 mg Klucel 25 mg cherry flavor 10 mg magnesium stearate 2 mg Red #40 Lake

TABLE 11.F Omeprazole (60 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 60 mg omeprazole  7.0 mEq or 350 mg Ca(OH)₂ 30 mgsucralose per tablet  3.0 mEq or 250 mg NaHCO₃ 40 mg Ac-Di-Sol 10.0 mEqor 600 mg total 30 mg antacid pregelatinized starch 30 mg Klucel 40 mgXylitab  7 mg mint flavor 10 mg magnesium stearate

TABLE 11.G Omeprazole (10 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 10 mg omeprazole 5.0 mEq or 250 mg Ca(OH)₂ 20 mgsucralose per tablet 2.9 mEq or 240 mg NaHCO₃ 40 mg Ac-Di-Sol 7.9 mEq or490 mg total 30 mg antacid pregelatinized starch 30 mg Klucel 15 mgcherry flavor  8 mg magnesium stearate  1 mg Red #40 Lake

TABLE 11.H Omeprazole (40 mg) Bite-Disintegration Chewable Tablet PPIAntacid Excipient 40 mg micro-  8.0 mEq or 400 mg Ca(OH)₂ 30 mgsucralose encapsulated  2.9 mEq or 240 mg NaHCO₃ 40 mg Ac-Di-Solomeprazole per 10.9 mEq or 1590 mg total 30 mg pregelatinized tabletantacid starch 30 mg Klucel 40 mg Xylitab  7 mg mint flavor 10 mgmagnesium stearate

Example 12 Powder for Suspension Formulations

The following specific formulations are provided by way of referenceonly and are not intended to limit the scope of the invention. Eachformulation contains therapeutically effective doses of PPI andsufficient antacid to prevent acid degradation of at least some of thePPI by raising the pH of gastric fluid. The PPI can be in a micronizedform.

TABLE 12.A Microencapsulated Omeprazole (20/40/60/120 mg) Powder forSuspension 1 2 3 4 5 6 7 8 9 10 Microencapsulated 20 20 20 40 40 40 6060 120 120 Omeprazole Sodium Bicarbonate 200 220 300 140 160 200 300 280150 200 Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 150Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol 300 (sweetener)1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder 10001000 1000 1000 1000 1000 1000 1000 1000 1000 (sweetener) Sucralose(sweetener) 60 100 150 75 100 70 80 130 125 80 Xanthan Gum 10 55 31 8039 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 77 38 35 62 Peppermint13 10 29 28 36 42 56 17 16 50 Total Weight 2586 2590 2755 2645 2705 27502815 2800 2610 2880 Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.210.5

TABLE 12.B Omeprazole (20 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10Omeprazole 20 20 20 20 20 20 20 20 20 20 Sodium Bicarbonate 200 220 300140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 10001000 Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 XanthanGum 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 77 3835 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2586 25902755 2625 2685 2730 2775 2760 2510 2780 Total ANC 11.0 8.4 8.7 10.2 9.710.5 9.4 10.5 5.2 10.5

TABLE 12.C Omeprazole (40 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10Omeprazole 40 40 40 40 40 40 40 40 40 40 Sodium Bicarbonate 200 220 300140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 10001000 Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 XanthanGum 75 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 7738 35 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2606 26102775 2645 2705 2750 2795 2780 2530 2800 Total ANC 11.0 8.4 8.7 10.2 9.710.5 9.4 10.5 5.2 10.5

TABLE 12.D Omeprazole (60 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10Omeprazole 60 60 60 60 60 60 60 60 60 60 Sodium Bicarbonate 200 220 300140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 10001000 Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 XanthanGum 75 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 7738 35 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2626 26302795 2665 2725 2770 2815 2800 2550 2820 Total ANC 11.0 8.4 8.7 10.2 9.710.5 9.4 10.5 5.2 10.5

Example 13 Naked or Microencapsulated Omeprazole 40 mg Chewable Tablets,Capsules, and Caplets are Pharmacokinetically Bioequivalent to Prilosec®Delayed-Release Capsules 40 mg with Respect to Area Under the Curve(AUC)

This trial was conducted as an open-label, single-dose, crossover trial,with each subject receiving up to twelve different oral omeprazoleformulations, one in each of the twelve treatment periods. Each dose wasfollowed by a minimum 7-day washout. Omeprazole was administered at adose of 40 mg. The amount of antacid used in the formulations varied asset forth in Table 13A. All formulations were administered with about120 ml (4 oz) of water after an overnight fast and 1 hour prior to astandardized, high-fat breakfast. Within a given treatment period, thesame treatment was administered to all subjects.

The omeprazole was delivered as either Prilosec® or as animmediate-release formulation according to the invention (i.e. withoutan enteric coating). Omeprazole was formulated as uncoated ormicroencapsulated granules a powder in a capsule, a caplet or in acompressed chewable tablet.

Selection of the exact formulation for each treatment period is setforth in Table 13A, below.

TABLE 13A The pharmacokinetic release trial periods 1–12 with the testedomeprazole dosage forms. (All dosage forms contained 40 mg omeprazole asfollows: Prilosec ® 40 mg, or a capsule, tablet, or caplet form, 40 mg).Period Study Material 1 (Prilosec ®) Prilosec ® (40 mg omeprazole) 2(SAN - 10A) SAN - 10A Capsule, 21.1 mEq (420 mg SB & 470 mg MH) Utilizes<100 mesh MH 3 (SAN - 15A) Period 3 Tablet, 30.7 mEq (850 mg SB & 600 mgMH) “Naked” OME & MS95 MH 4 (SAN - 10B) SAN - 10B Capsule, 21.1 mEq (420mg SB & 470 mg MH) Utilizes <60 mesh MH 5 (SAN - 15B) Period 5 Tablet,30.7 mEq (850 mg SB & 600 mg MH) with Klucel eAPI & MS95 MH 6 (SAN -10J) SAN - 10J Capsule, 19.1 mEq (378 mg SB & 425 mg MH) Utilizes MS95MH 7 (SAN - 15C) Period 7 Tablet, 30.7 mEq (850 mg SB & 600 mg MH) withMethocel eAPI & MS95 MH 8 (SAN - 10H) SAN - 10H Capsule, 17.9 mEq (420mg SB & 375 mg MH) Utilizes <60 mesh MH 9 (SAN - 10BB) SAN - 10BBCapsule, 13.1 mEq (1100 mg SB) 10 (SAN - 15D) Period 10 Caplet, 18.8 mEq(280 mg SB & 450 mg MH) eAPI, MS95 MH & 4.9% disintegrant 11 (SAN - 10C)SAN - 10C Capsule, 10.5 mEq (880 mg SB) 12 (SAN - 15E) Period 12 Caplet,18.8 mEq (280 mg SB & 450 mg MH) eAPI, MS95 MH & 7.9% disintegrant

Volunteers were screened for up to 14 days before baseline measurementsof blood plasma levels of omeprazole. In each period, a standardizedhigh-fat breakfast was given in the clinic 1 hour after dosing ofomeprazole. Blood samples for determination of plasma omeprazoleconcentrations were collected for 12 hours post treatment.

Duration of Treatment

Including screening, subjects participated in this trial for up to 170days.

Design Rationale

This trial was designed to assess the pharmacokinetics ofimmediate-release omeprazole chewable tablets, oral capsule and capletsversus the Prilosec® 40 mg delayed-release formulation. The duration ofthe trial for each subject was approximately 24 weeks, including up to14 days for screening and a minimum 7 day wash-out period betweenomeprazole doses.

Data from 12 healthy male subjects were expected to provide adequatepower to assess pharmacokinetics and safety using descriptivestatistics. The descriptive statistics were assessed using thepharmacokinetic parameters: Tmax, Cmax, AUC(0-t), AUC(0-inf), T½ andkel. Safety evaluations were based on the occurrence (vel non) ofadverse events, blood chemistry and hematology, use of concomitantmedications and change from baseline in physical examination findingsand vital signs.

As the study employed a single dose of omeprazole for each period ofdosing, the analysis focused on Day 1 of dosing.

The time of drug administration (after an overnight fast and 1 hourprior to a meal) meets the regulatory guidance for bioequivalence(fasting) and anticipates actual use.

Treatments Administered:

The treatments administered to subjects in this trial are listed inTable 13A, above. In general, the treatment protocol entailed a 14 dayassessment period, followed by a first period (Period 1) in whichPrilosec® 40 mg delayed release capsule was administered to thesubjects, after an overnight fast, and 1 hour prior to a standardizedhigh-fat breakfast. Plasma sampling was conducted for 6 hour post-dose.Period 1 was followed by a 7-14 day washout period, during which theplasma levels of omeprazole were expected to decrease to a steadybaseline. The second through twelfth periods (Periods 2-12) wereconducted in a similar manner to Period 1, in each period substituting adosage form according to the invention for the delayed-releaseformulation used in Period 1. The specific dosage forms used in thestudy are set forth in Table 13A, above. Each of the 12 healthy malevolunteers received the same course of treatment without randomization.

Pharmacokinetic Sampling, Analytical Methods, and Parameters

Blood samples (3 mL) were obtained by venipuncture within 30 minutesbefore each dose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240,300, 360 minutes (6 hours) after delivery of each dose during each trialperiod. Zero time was the time that the subject swallowed a capsule,caplet or chewable tablet of trial drug.

Plasma omeprazole concentrations were measured using a previouslyvalidated liquid chromatography mass spectrometry (LC-MSIMS) assay (MDSPharma Services, Lincoln, Nebr.). The linear assay range was 5.0 to 750ng/mL.

The following pharmacokinetic parameters were measured for each subject:

-   -   Plasma omeprazole concentration at each sampling time    -   Peak omeprazole plasma concentration (Cmax) and the time at        which Cmax is observed (Tmax) obtained directly from the data        without interpolation    -   Terminal elimination rate constant (Kel) determined from a        log-linear regression analysis of the terminal plasma omeprazole        concentrations    -   Half-life of drug elimination (T %) calculated as 0.693/Kel    -   Area under the plasma drug time-concentration curve calculated        from 0 time to last time point evaluated [AUC(0-t)] calculated        using the trapezoidal rule with the plasma concentration at time        t being the last measurable concentration    -   Area under the plasma drug time-concentration curve calculated        from 0 time and extrapolated to infinity [AUC(0-inf)] calculated        as AUC(0-t)+Ct/Kel, where Ct is the last measurable plasma        concentration (at time t) and Kel is the terminal elimination        rate constant defined above        Primary Endpoint

The primary pharmacokinetic endpoint was the bioavailability ofomeprazole [AUC(0-inf)].

Pharmacokinetic Analysis

For the analysis of data collected on Day 1 of each period (pre-mealdosing), an analysis of variance (ANOVA) model was used to test thebioequivalence of each of the tested drug formulations. The modelincluded the following factors: treatment, period, sequence, and subjectnested within sequence. Ninety percent confidence intervals (CIs) fortreatment differences were calculated; the endpoints of these CIs werethen reverse transformed to represent CIs about the percent mean ratioson the original scale. With respect to AUC(0-inf) and Cmax, equivalencewas declared for each parameter if the bounds of the 90% CIs for thepercent mean ratio, comparing a composition according to the invention(Periods 2-12) with Prilosec, were between 80% and 125%.

Determination of Sample Size

A sample size of 12 initial healthy male subjects was consideredsufficient to ensure that at least 5 subjects finished the entire trial.

Pharmacokinetic Results

Pharmacokinetic results are presented in Table 13 B. and FIGS. 14-16,18, 19, 21, 22, 23.

TABLE 13.B Pharmacokinetic Release Profiles of Formulated OME andPrilosec 40 mg Study of Periods 1–12 Intervals (Minutes) ng/mLPeriod/Test Dosage Day 0 5 10 15 20 30 45 60 Mean Prilosec (P1) 1 0 0 00 2 20 205 485 Min Prilosec (P1) 1 0 0 0 0 0 0 37 104 Max Prilosec (P1)1 0 0 0 0 15 80 543 1474 Mean Capsule (P2) (SAN-10A) 1 0 0 29 176 6471043 1022 929 Min Capsule (P2) (SAN-10A) 1 0 0 0 0 11 26 152 158 MaxCapsule (P2) (SAN-15A) 1 0 0 340 888 1600 2351 2696 2295 Mean Chew Tab(P3) (SAN-15A) 1 0 80 642 921 1001 1092 939 800 Min Chew Tab (P3)(SAN-15A) 1 0 0 73 149 188 177 145 132 Max Chew Tab (P3) (SAN-15A) 1 0352 1321 1779 2073 2705 2571 2311 Mean Capsule (P4) (SAN-10B) 1 0 0 36192 413 623 698 682 Min Capsule (P4) (SAN-10B) 1 0 0 0 8 19 94 128 175Max Capsule (P4) (SAN-10B) 1 0 0 373 966 1403 1727 1801 1792 Mean ChewTab (P5) (SAN-15B) 1 0 53 473 820 956 958 897 856 Min Chew Tab (P5)(SAN-15B) 1 0 0 36 330 428 379 227 167 Max Chew Tab (P5) (SAN-15B) 1 0150 1073 1770 2110 2327 2848 3097 Mean Capsule (P6) (SAN-10E) 1 0 0 1 65502 1007 969 818 Min Capsule (P6) (SAN-10E) 1 0 0 0 0 14 47 156 170 MaxCapsule (P6) (SAN-10E) 1 0 0 10 173 1126 2323 2721 2474 Mean Chew Tab(P7) (SAN-15C) 1 0 65 706 1396 1386 1230 1048 852 Min Chew Tab (P7)(SAN-15C) 1 0 0 191 473 711 515 321 226 Max Chew Tab (P7) (SAN-15C) 1 0382 1172 2807 2306 2580 2358 2117 Mean Capsule (P8) (SAN-10H) 1 0 0 136293 586 893 848 823 Min Capsule (P8) (SAN-10H) 1 0 0 0 11 57 266 196 197Max Capsule (P8) (SAN-10H) 1 0 0 451 1100 1428 1697 1627 1871 MeanCapsule (P9) (SAN-10BB) 1 0 0 37 286 867 1198 1111 936 Min Capsule (P9)(SAN-10BB) 1 0 0 0 24 120 299 275 204 Max Capsule (P9) (SAN-10BB) 1 0 0172 809 1624 2305 1957 2222 Mean Caplet (P10) (SAN-15D) 1 0 56 184 269199 213 235 322 Min Caplet (P10) (SAN-15D) 1 0 0 5 23 28 49 48 56 MaxCaplet (P10) (SAN-15D) 1 0 440 1256 1518 744 595 469 1013 Mean Capsule(P11) (SAN-10C) 1 0 1 33 292 1027 1026 868 767 Min Capsule (P11)(SAN-10C) 1 0 0 0 26 52 267 337 237 Max Capsule (P11) (SAN-10C) 1 0 7196 827 2024 2056 1729 1992 Mean Caplet (P12) (SAN-15E) 1 0 5 43 81 116327 540 583 Cmax Tmax ng/mL Period/Test Dosage Day 90 120 180 240 300360 N (ng/mL) (hr) Mean Prilosec (P1) 1 991 679 417 265 203 143 12 10611.38 Min Prilosec (P1) 1 241 127 37 8 8 0 12 273 1.00 Max Prilosec (P1)1 2994 2146 1596 1093 1081 707 12 2994 1.50 Mean Capsule (P2) (SAN- 1733 504 309 226 149 107 12 1155 0.76 10A) Min Capsule (P2) (SAN- 1 96 5119 6 0 0 12 285 0.63 10A) Max Capsule (P2) (SAN- 1 2133 1670 1362 1215835 676 12 2696 1.50 15A) Mean Chew Tab (P3) (SAN- 1 597 441 280 193 12995 12 1201 0.54 15A) Min Chew Tab (P3) (SAN- 1 71 42 9 0 0 0 12 196 0.5015A) Max Chew Tab (P3) (SAN- 1 2133 1701 1322 999 709 587 12 2705 1.5015A) Mean Capsule (P4) (SAN- 1 799 616 371 274 182 147 12 990 1.22 10B)Min Capsule (P4) (SAN- 1 120 44 9 0 0 0 12 222 0.33 10B) Max Capsule(P4) (SAN- 1 2358 2168 1691 1491 983 900 12 2358 2.00 10B) Mean Chew Tab(P3) (SAN- 1 633 467 305 226 148 122 12 1192 0.50 15C) Min Chew Tab (P3)(SAN- 1 70 29 14 7 0 0 12 428 0.17 15C) Max Chew Tab (P3) (SAN- 1 25862058 1532 1279 788 744 12 3097 1.00 15C) Mean Capsule (P6) (SAN-10E) 1648 436 284 175 137 89 12 1130 0.78 Min Capsule (P6) (SAN-10E) 1 92 5120 0 0 0 12 399 0.33 Max Capsule (P6) (SAN-10E) 1 2415 1879 1323 994 858590 12 2721 1.50 Mean Chew Tab (P7) 1 610 436 295 217 161 112 11 15500.33 Min Chew Tab (P7) 1 67 31 7 0 0 0 11 711 0.25 Max Chew Tab (P7) 12244 1538 1279 1069 760 596 11 2807 0.50 Mean Capsule (P8) (SAN- 1 724516 323 192 135 102 8 1128 0.78 10H) Min Capsule (P8) (SAN- 1 87 48 14 00 0 8 362 0.25 10H) Max Capsule (P8) (SAN- 1 2196 1848 1426 882 685 5568 2196 1.50 10H) Mean Capsule (P9) (SAN- 1 652 519 323 234 161 118 81364 0.55 10BB) Min Capsule (P9) (SAN- 1 120 82 20 0 0 0 8 535 0.3310BB) Max Capsule (P9) (SAN- 1 1806 1755 1269 1074 824 637 8 2305 0.7510BB) Mean Caplet (P10) 1 699 598 430 271 178 136 8 111 1.59 Min Caplet(P10) 1 143 97 42 21 10 6 8 531 0.25 Max Caplet (P10) 1 1440 1850 14041036 749 633 8 1850 3.00 Mean Capsule (P11) (SAN- 1 591 473 286 204 133111 7 1378 0.57 10C) Min Capsule (P11) (SAN- 1 74 41 16 0 0 0 7 414 0.3310C) Max Capsule (P11) (SAN- 1 1842 1826 1214 1004 657 592 7 2056 1.0010C) Mean Caplet (P12) 1 909 531 320 196 143 110 8 1083 1.59Formulations in Tables 13A and 13B were prepared according to thefollowing protocols:Preparation of Capsules

SAN-10A, SAN-10B, SAN-10BB and SAN-10K capsules were prepared on a 1.5kg batch size in a 6 quart planetary mixer. The grade of each ingredientis shown in Table 13C below. Omeprazole USP is micronized omeprazoleobtained from UQUIFA, holder of the Type II DMF for micronizedomeprazole.

About half the sodium bicarbonate (#2 USP) was blended together withomeprazole and then with the other half of the sodium bicarbonate.Magnesium hydroxide was screened through a 100 or 60 US mesh screen andthen charged into the planetary mixer. Then the entire blend was passedthrough a #20 mesh s/s screen and reintroduced into the Planetary Mixerand mixed for 10 minutes. Magnesium stearate was screened through a #40mesh s/s screen directly into the Planetary Mixer and blended for 3minutes. The mixture was then encapsulated in hard gelatin capsules,size #00, using a Profill® manual encapsulator. The amount of eachingredient used in SAN-10A, SAN-10B, SAN-10BB and SAN-10K capsules isset forth in Table 13C.

TABLE 13C SAN-10A SAN-10B SAN-10BB SAN-10K Ingredients mg/caps % mg/caps% mg/caps % mg/caps % Omeprazole USP 40.8 4.2 40.8 4.2 40.8 3.5 40.8 4.3Sodium 420 43.3 420 43.3 1100 94.0 882 93 Bicarbonate #2 USP Magnesium470 48.4 0 0 0 0 0 0 Hydroxide (screened) 100 mesh Magnesium 0 0 47048.4 0 0 0 0 Hydroxide (screened) 60 mesh Croscarmellose 30 3.1 30 3.120 1.7 20 2.1 Sodium NF Magnesium 10 1.0 10 1.0 10 0.9 10 1.0 StearateNF Totals 970.8 100.0 970.8 100 mg/caps % mg/caps %

SAN-10E and SAN-10H were prepared in a manner similar to that describedfor SAN-10A, etc., above, except that SAN-10E used a special grade ofmagnesium hydroxide (MS-95), which is a spray-dried magnesium hydroxidecontaining 95% magnesium hydroxide and 5% pre-gelatinized starch.SAN-10H is a blend fortified with croscarmellose sodium, which wasdeveloped for encapsulation on a Zanasi LZ64 dosator-type encapsulator.The amount of each ingredient is set forth in Table 13C. Both SAN-10Eand SAN-10H were encapsulated in hard gelatin capsules, size #00.SAN-10E capsules were encapsulated using the Profill® hand encapsulator.SAN-10H capsules were encapsulated using the Zansi LZ64 dosator typeencapsulator. The amount of each ingredient per capsule is set forth inTable 13C below.

TABLE 13D SAN-10E SAN-10H Ingredients mg/caps % mg/caps % Omeprazole USP40.8 4.5 40.8 4.4 Sodium 378 42.0 420 45.6 Bicarbonate #2 USP Magnesium0 0 0 0 Hydroxide (screened) 100 mesh Magnesium 0 0 375 40.6 Hydroxide(screened) 60 mesh Magnesium 447.4 49.8 0 0 Hydroxide MS-95Croscarmellose 27 3.0 82 8.9 Sodium NF Magnesium 6 0.7 5 0.5 Stearate NFTotals 899.2 100.0 922.8 100.0Preparation of Chewable Tablets

Micronized omeprazole USP (UQUIFA) was microencapsulated withhydroxypropylcellulose (HPC) using a spray drying process. The grade ofHPC was Klucel®, EF. The amount of each excipient used is set forth inTable 13E.

TABLE 13E Weight (%) Weigh Feed (%) Dry Excipient Suspension ProductFunction Omeprazole USP 6.00% 37.00% API HPC Klucel ® EF, NF 10.0 61.6Coating Material Sodium Bicarbonate, USP 0.23 1.4 pH Adjuster PurifiedWater, USP 83.8 N/A Suspension Totals 100.00% 100.00% Medium

HPC was added slowly to purified water and mixed until dissolved. Sodiumbicarbonate and omeprazole were then added slowly to preventagglomeration. The spray composition was then screened prior tointroducing it into the spray drier. The spray composition was thenspray dried using a Niro® spray drier, which is equipped with a rotaryspray atomizer. The final omeprazole content of the microencapsulatedformulation is 37%.

Microencapsulated omeprazole was combined with about half the antacidexcipient were blended to homogeneity to form an omeprazole pre-blend.The flavor components were next mixed with one another to form a flavorpre-blend. The omeprazole pre-blend and the flavor pre-blend werecombined to form a main blend. Finally, a lubricant, magnesium stearatewas added to the main blend to form the final blend. Tablets were formedon a commercial Fette press. The amount of the active ingredient andexcipients used are set forth in Table 13A, above.

Conclusion

Naked or microencapsulated omeprazole 40 mg in Tablet, Capsule andCaplet forms (Periods 2-12) were bioequivalent to Prilosec® Capsules 40mg with regard to AUC(0-inf). See FIGS. 14 and 15. The two treatmentswere not equivalent with regard to peak plasma concentration, Cmax. Thisdifference in Cmax had no apparent effect on the pharmacodynamics orsafety of the 40 mg formulation in this trial. The two treatments werealso not equivalent with regard to pharmacokinetic release profiles.

Example 14A Formulation of SAN-7F (20 mg Omeprazole Capsules)

A 1300 kg lot of 20 mg omeprazole capsules was manufactured under cGMPconditions. The formulation is set forth in Table 14A, below:

TABLE 14A Amount Required % for 1300 kg Ingredient Weight mg/CapsuleBatch (kg) Omeprazole, USP 1.8% 20.4 mg/cap 22.9 kg Sodium Bicarbonate,USP 94.8 1100 1232 #2 Croscarmellose Sodium, NF 2.6 30 33.6 MagnesiumStearate, NF 0.9 10 11.2 Totals 100 1160.4 1300

The following ingredients were added to a tote (tote #1) in thefollowing order: Sodium bicarbonate (about 25% of total), omeprazoleUSP, sodium bicarbonate (about 25% of total). The contents of tote #1were then charged into a 60 ft³ V-blender through a Comil® powder millequipped with a 16 mesh equivalent screen, operating the powder screenat a speed setting of high (800 rpm). The contents were mixed for 5minutes at 8 rpm. About 25% of the total amount of sodium bicarbonatewas then charged into a tote (tote #2). Then the contents of theV-blender were charged into tote #2. The contents of tote #2 were thenpassed through a Comil® powder mill equipped with a 16 mesh equivalentscreen at a speed setting of high (800 rpm).

Next, croscarmellose sodium and the remaining amount of sodiumbicarbonate were charged into tote #1. The contents of tote #1 were thenpassed through a Comil® powder mill equipped with a 16 mesh equivalentscreen at a speed setting of high (800 rpm) and charged into theV-blender. The mixture was then blended for 15 minutes a 8 rpm. Thenmagnesium stearate was screened through a #30 mesh hand screen andcharged into the V-blender. The resulting mixture was then blended for 3minutes at 8 rpm. The contents of the V-blender were then dischargedinto labeled containers lined with inner clear polyethylene bagoverwrapped with an outer black polyethylene bag. The resulting mixturewas encapsulated on a H&K 1200® dosing disc/tamping pin-typeencapsulator using hard gelatin capsules size #00.

Critical Encapsulation Process Parameters

Encapsulator powder bed depth

Dosing disc size

Tamping pin settings

The encapsulator powder bed depth, dosing disc size, and tamping pinsettings are all controlling factors in achieving target capsule weightsand maintaining the consistency of those weights throughout theencapsulation process. The encapsulator powder bed depth is maintainedat a uniform level above the dosing disc. The dosing disc size is fixedby the dosing disc thickness, which is 24 mm for the SAN-7F Capsules 20mg process. Tamping pin settings are adjusted to achieve the desiredtarget weight and maintain consistent weight uniformity.

Example 14B Clinical Trial with SAN-7F 20 mg Capsule

Trial Objectives

Primary Objective

The primary objective was to test the hypothesis that SAN-7F Capsules 20mg (omeprazole 20 mg/dose) are pharmacokinetically bioequivalent toPrilosec 20 mg with respect to area under the curve (AUC).

Secondary Objectives:

The secondary objectives were:

1. To assess whether SAN-7F Capsules 20 mg are pharmacodynamicallybioequivalent to Prilosec 20 mg with respect to percent decrease fromBaseline in integrated gastric acidity; and

2. To compare the pharmacokinetics of SAN-7F Capsules 20 mg administeredpost-meal to the pharmacokinetics of SAN-7F Capsules 20 mg administeredpre-meal.

Design:

This was an open-label, randomized, 2-period crossover trial to evaluatethe pharmacokinetics, pharmacodynamics, and safety of 7 consecutivedaily doses of SAN-7F. Capsules containing 20 mg omeprazole werecompared to 7 consecutive daily doses of Prilosec 20 mg in healthysubjects. A comparison of pharmacokinetic parameters for SAN-7Fadministered before versus after a meal was conducted.

Volunteers were screened within 21 days before baseline measurements(gastric pH, vital signs). Gastric pH was recorded for 24 hours beforethe first dose of trial drug. In Period 1, subjects received SAN-7F 20mg or Prilosec 20 mg, as randomized, 1 hour before breakfast for 7consecutive days. A standardized high-fat breakfast was given in theclinic 1 hour after dosing on Days 1 and 7, or 1 hour after water forbaseline assessment. Standardized lunch and dinner were also given 5 and10 hours post-dose at baseline and on Days 1 and 7 in the clinic. Bloodsamples for determination of plasma omeprazole concentrations werecollected for 12 hours, and gastric pH was measured for 24 hours afterthe doses on Days 1 and 7. Subjects who had received SAN-7F 20 mg(omeprazole) in Period 1 were given an eighth dose (Day 8) 1 hour afterthe start of the standardized high-fat breakfast. Blood samples werecollected for 12 hours after the eighth dose (see Section 9.8 regardingthe Dose 8 deviation). After a 10- to 14-day washout period, subjectsreturned for Period 2 and received an alternate treatment from thatreceived in Period 1. Procedures in Period 2 were identical to those inPeriod 1, except that there was no eighth dose of SAN-7F 20 mg.

Number of Subjects (Planned and Analyzed)

Thirty-six subjects were dosed and 30 subjects complete 7 days of dosingin each period of the trial. Thirty subjects were included in thepharmacokinetic analysis and 25 subjects were included in thepharmacodynamic analysis for Doses 1 and 7. Because of an error inpost-meal administration of SAN-7F Capsules 20 mg on Day 8 (Period 1),pharmacokinetic analyses for post-meal administration of SAN-7F Capsules20 mg were not completed.

Duration of Treatment

Including screening, subjects participated in this trial for up to 40days.

Design Rationale:

A 2-period crossover design is consistent with FDA guidance for theassessment of comparative pharmacokinetics in healthy volunteers.

Data from 24 subjects were expected to provide adequate power to showbioequivalence between the 2 formulations evaluated in this trial, basedon the intersubject variability with regard to the pharmacokinetics[AUC(0-inf)] and pharmacodynamics of omeprazole in previous trials.

The 20-mg dose was studied in support of using a SAN-7F Capsules 20 mgomeprazole dose for short-term treatment of active duodenal ulcer,treatment of heartburn and other symptoms associated withgastroesophageal reflux disease (GERD), short-term treatment of erosiveesophagitis, and maintenance of healing of erosive esophagitis.

The primary analysis focused on Day 7 of dosing, since thepharmacokinetics of omeprazole are known to change with repeated dosingand the pharmacodynamic effects are maximal by the seventh day ofconsecutive daily dosing (steady state).

The time of drug administration (after an overnight fast and 1 hourprior to a meal) meets the regulatory guidance for bioequivalence(fasting) and anticipates actual use.

In Period 1 at steady state (Day 8), the pharmacokinetics of SAN-7FCapsules 20 mg given post-meal were compared to those of SAN-7F 20 mggiven pre-meal (Day 7). This comparison was conducted to evaluate theeffect of food on the bioavailability of SAN-7F Capsules 20 mg. Thisportion of the protocol was not conducted correctly during this period.

Treatments Administered:

The treatments administered to subjects in this trial are listed in thetable below.

TABLE 14B Treatment Description Treatment Treatment Description SAN-7FSAN-7F Capsules (omeprazole immediate- release capsules) 20 mgadministered orally with 120 mL water each morning after an overnightfast, 1 hour before starting a standardized high fat breakfast. PrilosecPrilosec Capsules (omeprazole delayed-release capsules) 20 mgadministered orally with 120 mL water each morning after an overnightfast, 1 hour before starting a standardized high-fat breakfast. SAN-7FDose 8 SAN-7F Capsules (omeprazole immediate- release capsules) 20 mg,administered orally with 120 mL water on Day 8 in Period 1, 1 hour afterstarting a standardized high-fat breakfast.The description below represents the schedule of events:Events:1. Period 1—SAN-7F Capsules 20 mg or Prilosec 20 mg (by randomization).

Location of the lower esophageal sphincter (LES) on the day the subjectchecked into the clinic (Day minus 2).

Seven consecutive single daily AM doses pre-meal (plus Dose 8 on Day 8post-meal only for subjects receiving SAN-7F Capsules 20 mg).Twelve-hour PK sampling after Doses 1, 7, and 8 (SAN-7F Capsules 20 mgonly). Twenty-four-hour gastric pH monitoring during Baseline startingon Day minus 1, and during treatment starting on Day 1 (Dose 1) and Day7 (Dose 7).

2. 10-14 Day Washout

3. Period 2—SAN-7F Capsules 20 mg or Prilosec 20 mg—Alternativeformulation to that in Period 1. Seven consecutive single daily AM dosespre-meal. Twelve-hour PK sampling after Doses 1 and 7. Twenty-four-hourgastric pH monitoring during Baseline starting on Day minus 1, andduring treatment starting on Day 1 (Dose 1) and Day 7 (Dose 7).Pharmacokinetic Sampling, Analytical Methods, and Parameters

Blood samples (3 mL) were obtained by venipuncture within 30 minutesbefore each dose and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180,210, 240, 300, 360, 420, 480, 540, 600, 660, and 720 minutes (12 hours)after each dose on Days 1 and 7 of both periods and Day 8 of Period 1(for SAN-7F Capsules 20 mg). Zero time was the time that the subjectswallowed a capsule of trial drug.

Plasma omeprazole concentrations were measured using a validated liquidchromatography mass spectrometry (LC-MSIMS) assay (MDS Pharma Services,Lincoln, Nebr.). The linear assay range was 5.0 to 750 ng/mL.

The following pharmacokinetic parameters were measured for each subject:

-   -   Plasma omeprazole concentration at each sampling time    -   Peak omeprazole plasma concentration (Cmax) and the time at        which Cmax is observed (Tmax) obtained directly from the data        without interpolation    -   Terminal elimination rate constant (Kel) determined from a        log-linear regression analysis of the terminal plasma omeprazole        concentrations    -   Half-life of drug elimination (T %) calculated as 0.693/Kel    -   Area under the plasma drug time-concentration curve calculated        from 0 time to last time point evaluated [AUC(0-t)] calculated        using the trapezoidal rule with the plasma concentration at time        t being the last measurable concentration    -   Area under the plasma drug time-concentration curve calculated        from 0 time and extrapolated to infinity [AUC(0-inf)] calculated        as AUC(0-t)+Ct/Kel, where Ct is the last measurable plasma        concentration and Kel is the terminal elimination rate constant        defined above        Measurement of Gastric pH

Subjects remained propped up in bed (about 45 degrees) from the time ofinitial gastric pH recording, through 5 hours post dose. Subjects werethen allowed restricted physical activity until bedtime, at which timethey were again propped up in bed (approximately 45 degrees) andremained in this position for the remainder of the pH monitoring period.Gastric pH data were collected every 4 seconds (this measured value wasthen imputed for each of the following 3 seconds by the software) usingan ambulatory pH recording system (Digitrapper@ 400, MedtronicFunctional Diagnostics, Inc, Shoreview, Minn. USA) with a disposableantimony electrode and an internal standard (Medtronic Zinetics 24@Single-Use pH Catheter with or without the lower esophageal [LES]locator). At the Period 1 check-in (Day minus 2), the LES was locatedmanometrically (Medtronic Polygram '98 for Windows v. 2.20) and thedistance from the upper border of the LES to the nares was recorded onthe CRF.

For all measurements of gastric pH, the electrode was placed in thestomach 10 cm below the upper border of the LES using measurementsdetermined at Day minus 2 of Period 1. The probe was insertedapproximately 1 hour prior to dosing and the proximal end was taped tothe side of the face to prevent shifting of the probe. Prior toinsertion, the electrode was calibrated at room temperature to pH 1 and7 using standard commercial polyelectrolyte solutions (Medtronic,Toronto). The software used to process the pH data corrected for thedifference between electrode calibration temperature (approximately 25°C.) and recording temperature (37° C.). Recordings continued fromapproximately 1 minute before until 24 hours after dosing (trial drug orwater during Baseline). Times for the following events were indicatedelectronically on the pH record using the following event markers:beginning of pH recording, dosing of trial drugs, initiation of eachmeal, and the end of the pH recording.

Readjustment of the gastric pH probe for any potential migration of thepH probe out of the stomach during evening hours was achieved using thefollowing procedures: During baseline periods before dosing, theDigitrappers were checked every hour from 16 hours to 24 hours afteradministering 120 mL water. If a pH value was >2.5 (1-minuteobservation), the subject was repositioned and asked to take 1 or moresips of water (≦60 mL total). If the pH did not decrease to ≦2.5 within5 minutes, the probe was partially withdrawn and then advanced to 10 cmbelow the upper border of the LES (the administration of ≦60 mL waterper hour was permitted to facilitate this procedure). If afterrepositioning the probe, the pH was not ≦2.5, no further adjustmentswere made during that hour. These procedures were repeated as necessaryduring the subsequent hours to ensure that the probe was properlyplaced. The number of times that the probe was adjusted (wateradministered or probe repositioned) was recorded on the CRF.

For all dosing periods, the Digitrappers were checked every hour from 16hours to 24 hours after administering the dose. If the pH was >5(1-minute observation), the subject was repositioned. If the pH did notdecrease to ≦5 within the next 5 minutes, the subject was administered≦60 ml of water. If the pH did not decrease to ≦5 within the next 1minute, the probe was partially withdrawn and then advanced to 10 cmbelow the upper border of the LES (≦60 mL of water may have beenadministered to facilitate this procedure). If after repositioning theprobe, the pH was still >5, no further adjustments were made during thathour. These procedures were repeated, as needed, during the subsequenthour(s) to assure that the probe was properly placed. The hourlyassessments and actions taken were recorded on the CRF.

Pharmacodynamic Parameters and Methodology

The following pharmacodynamic parameters were measured for each 24-hourperiod in 15-minute intervals:

-   -   Integrated gastric acidity (mmol*hr/L), calculated for each        15-minute interval during the 24-hour recording period, as        follows:    -   Acid concentration (mmol/L)=1000×10^(−pH)    -   Acidity (mmol*hr/L)=(acid concentration at time “t”+acid        concentration at time “t₁”)/2×(t−t₁), where t and t₁ are the        times of 2 consecutive pH measurements    -   Integrated gastric acidity (mmol*hr/L) calculated as the sum of        acidity over each 15-minute interval    -   Mean gastric acid concentration (mmol/t), calculated as        integrated gastric acidity for each 15-minute interval/0.25 hour    -   Median gastric pH, calculated for each 15-minute interval    -   Percent time gastric pH was ≦4, calculated for each 15-minute        interval

Values for gastric pH were recorded once every 4 seconds. The softwareused to process the record filled in the same value for the following 3seconds. Each record was divided into 15-minute intervals beginning withzero time as the recording interval prior to dosing. All pH valuesoutside the acceptable range of 0.5 to 7.5, inclusive, were excludedprior to analysis.

Missing (or excluded) values for gastric pH were handled as follows:

If pH values were missing in a 15-minute interval, integrated gastricacidity and mean gastric acid concentration were calculated byintegrating across the missing data; however, only the available valueswere used to calculate the percentage of time gastric pH was ≦4 and themedian gastric pH.

If all of the pH values were missing in an entire 15 minute interval,integrated gastric acidity, mean gastric acid concentration, andpercentage of time gastric pH was ≦4 were calculated as the mean of thevalues from the interval immediately preceding and immediately followingthe interval for which all pH values were missing. For an interval withall missing pH values, the median of all values from the intervalimmediately preceding and immediately following were assigned to theinterval with all missing values.

Primary Endpoint

The primary pharmacokinetic endpoint was the bioavailability ofomeprazole [AUC(0-inf)] after the seventh dose of each omeprazoleformulation.

Secondary Endpoints

The secondary endpoints were:

-   -   Peak plasma concentration (Cmax) after the seventh dose of each        omeprazole formulation.    -   AUC(0-inf) and Cmax after the first dose of each omeprazole        formulation.    -   All other pharmacokinetic parameters after the first and seventh        doses of each omeprazole formulation: Tmax, Kel, T_(1/2),        AUC(0-t).    -   All pharmacokinetic parameters obtained with SAN-7F Capsules 20        mg administered post-meal.        Pharmacokinetic Analysis

For the analysis of data collected on Days 1 and 7 of each period(pre-meal dosing), an analysis of variance (ANOVA) model was used totest the bioequivalence of SAN-7F Capsules 20 mg and Prilosec, using thenatural logarithmic transformation of AUC(0-inf) and Cmax. The modelincluded the following factors: treatment, period, sequence, and subjectnested within sequence. Ninety percent confidence intervals (CIs) fortreatment differences were calculated; the endpoints of these CIs werethen reverse transformed to represent CIs about the percent mean ratioson the original scale. With respect to AUC(0-inf) and Cmax, equivalencewas declared for each parameter, if the bounds of the 90% CIs for thepercent mean ratio, SAN-7F to Prilosec, were between 80% and 125%.

Pharmacodynamic Statistical and Analytical Plan

Pharmacodynamic Endpoints

Primary Endpoint

The primary pharmacodynamic endpoint was the percent decrease fromBaseline in integrated gastric acidity for the 24-hour interval afterthe seventh dose of each omeprazole formulation.

Secondary Endpoint

The secondary pharmacodynamic endpoint was the percent decrease fromBaseline in integrated gastric acidity for the 24-hour interval afterthe first dose of each omeprazole formulation.

Other Pharmacodynamic Parameters (24-Hour Post-Dose Intervals)

Mean gastric acid concentration (mM)

Median gastric pH

Percent time gastric pH≦4

Pharmacodynamic Analysis

The pharmacodynamic effects of SAN-7F Capsules 20 mg and Prilosec 20 mgduring the 24-hour post-dose recording period were assessed after thefirst and seventh doses by evaluating the following parameters:integrated gastric acidity, mean gastric acid concentration, mediangastric pH, and the percentage of time gastric pH was ≦4 for the 24-hourperiod.

Evaluation of Period Effect

Prior to evaluating the pharmacodynamic effects of SAN-7F Capsules andPrilosec with respect to integrated gastric acidity, the possibility ofa period effect was assessed using an ANOVA model that included factorsfor period and subject, fit to the 24-hour baseline values forintegrated gastric acidity for each of the 2 periods. If nostatistically significant difference was found between the 2 baselinevalues, it was concluded that there was no period effect. In this case,the mean of the 2 baseline values was used as the baseline value foreach subject. If a statistically significant difference was foundbetween the baseline values, it would be concluded that there was aperiod effect. In this case, integrated gastric acidity was adjusted forthe period effect in the statistical analysis by analyzing the percentdecrease from the corresponding baseline value for each subject.

Analysis of Pharmacodynamic Endpoints

The analysis of integrated gastric acidity for the 24-hour periodfollowing dosing was conducted on the percent decrease from Baseline onDays 1 and 7 calculated for each subject as 100×[Baseline−Day 1 (or Day7)]/Baseline.

An ANOVA model was used to test the pharmacodynamic equivalence ofSAN-7F. Capsules and Prilosec, using the natural logarithmictransformation of percent decrease from Baseline in integrated gastricacidity. The model included the following factors: treatment, period,sequence, and subject nested within sequence. Ninety percent confidenceintervals (CIs) for treatment differences were calculated; the endpointsof these CIs were then reverse transformed to represent CIs about thepercent mean ratios on the original scale. Pharmacodynamic equivalencewas declared if the bounds of the 90% CIs for the percent mean ratio ofpercent decrease from Baseline in integrated gastric acidity, SAN-7F toPrilosec, were between 80% and 125%.

Descriptive Analyses

The ratio of the percent decrease from Baseline for integrated gastricacidity for the 24-hour period following the first and seventh doseswith SAN-7F Capsules and Prilosec was calculated for each subject as:percent decrease from Baseline for SAN-7F/percent decrease from Baselinefor Prilosec using the appropriate baseline value. The medians andboundaries of the inter-quartile range (25th and 75th percentiles) ofthe ratios for all subjects were tabulated.

Analyses of Other Pharmacodynamic Parameters

The ratio of the percent decrease from Baseline for mean gastric acidconcentration and for the percentage of time gastric pH was ≦4 for the24 hour period following dosing with SAN-7F Capsules and Prilosec wascalculated for each subject as: percent decrease from Baseline forSAN-7F/percent decrease from Baseline for Prilosec (using theappropriate baseline value). For median gastric pH, the ratio of theincrease from Baseline for SAN-7F and Prilosec was calculated for eachsubject (using the appropriate baseline value) as: increase fromBaseline for SAN-7F/increase from Baseline for Prilosec. The medians andboundaries of the inter-quartile range (25th and 75th percentiles) ofthe ratios for all subjects were tabulated.

Disposition of Subjects

Thirty-six subjects entered the trial and received at least one dose oftrial drug; 30 subjects completed the trial.

TABLE 14.C Summary of Subject Disposition n % Subjects who received atleast one dose of either trial 36 100.0 drug Subjects who completed both7-day treatment 30 83.3 periods Subjects who received 8 doses of SAN-7F20 mg* 22 61.1 Subjects who withdrew 6 16.7 *Includes 15 subjects whoreceived an eighth dose of SAN-7F 20 mg on Day 9 but no dose on Day 8 inPeriod 1 and 7 other subjects who received 8 consecutive daily dose ofSAN-7F 20 mg in Period 2.Pharmacokinetic Results

Pharmacokinetic results are presented the in Table 14.D. and FIGS. 16,17, 19, 20, 22 and 23.

After one dose, SAN-7F Capsules 20 mg and Prilosec 20 mg werebioequivalent with respect to AUC. The percent mean ratio of SAN-7F 20mg to Prilosec 20 mg was 105.31% for AUC(0-inf) with the bounds of the90% CI between 80% and 125% (98.94% and 112.09%). As expected for theimmediate-release product, the Cmax for SAN-7F 20 mg was higher than forPrilosec 20 mg (percent mean ratio of 148.49%, 90% CI of 129.16% to170.72%). The Tmax for SAN-7F was shorter than the Tmax for Prilosec(p<0.001; ANOVA).

Pharmacokinetic Conclusions

After the first dose and at steady state (Day 7), SAN-7F Capsules 20 mgwere equivalent to Prilosec 20 mg with respect to [AUC(0-inf)] (theprimary pharmacokinetic endpoint). The 2 treatments were not equivalentwith respect to Cmax on Days 1 and 7 with the percent mean ratio of 148%on Day 1 and 145% on Day 7. The Tmax was shorter for theimmediate-release product on Days 1 and 7 (p<0.001).

Pharmacodynamic Conclusions

On Day 7 of dosing, SAN-7F Capsules 20 mg were found equivalent toPrilosec 20 mg with regard to the primary pharmacodynamic endpoint,percent decrease from Baseline in integrated gastric acidity over 24hours. SAN-7F 20 mg and Prilosec 20 mg both decreased integrated gastricacidity by approximately 70% from Baseline at Day 7.

Trial Conclusion

Since comparisons in this trial involved a delayed-release formulation(Prilosec 20 mg) and an immediate-release formulation (SAN-7F Capsules20 mg), it was anticipated that the Tmax would occur earlier and theCmax would be higher for SAN-7F 20 mg than for Prilosec 20 mg. It wasalso expected that the 2 products would be equivalent with regard to AUCand, therefore, also with regard to their pharmacodynamic effects.

As anticipated, SAN-7F 20 mg was found equivalent to Prilosec 20 mg onDay 7 (and Day 1) of dosing with regard to AUC (0-inf) and equivalent atDay 7 with regard to percent decrease from Baseline in integratedgastric acidity over 24 hours. For Cmax, the upper bound of the 90%confidence interval for the percent mean ratio exceeded 125% on Days 1and 7. The pharmacodynamic data show that SAN-7F 20 mg and Prilosec 20mg were equally effective in decreasing integrated gastric acidity atsteady state (Day 7).

Both SAN-7F Capsules 20 mg and Prilosec 20 mg were well tolerated duringthe 7-day to 9-day dosing periods in this trial. No meaningfuldifferences between the treatments were observed with respect to safety.

TABLE 14.D 20 mg PK Summary for Day 1 and 7 (S7F = SAN-7F; Pr =Prilosec ®) ng Intervals (minutes) Drug mL Day 0 5 10 15 20 30 45 60 90120 150 180 S7F Mean 1 0 0 11 111 202 388 320 274 177 83 55 35 S7F Min 10 0 0 0 0 0 0 94 36 0 9 0 S7F Max 1 0 0 110 1090 927 1090 958 775 466246 181 120 S7F Mean 7 0 4 23 125 231 418 417 384 391 245 169 123 S7FMin 7 0 0 0 0 0 0 0 7 22 53 28 15 S7F Max 7 0 120 257 721 1130 1530 12401080 1270 735 576 473 Pr Mean 1 0 0 0 0 1 17 87 171 309 160 96 68 Pr Min1 0 0 0 0 0 0 0 0 81 50 23 13 Pr Max 1 0 0 0 0 27 205 319 441 794 622394 301 Pr Mean 7 0 0 0 1 8 76 222 292 380 277 194 145 Pr Min 7 0 0 0 00 0 0 0 0 62 43 25 Pr Max 7 12 8 8 12 88 333 994 988 1220 775 560 420 20mg PK Summary for Day 1 and 7 (Continued) (S7F = SAN-7F; Pr =Prilosec ®, 40 mg). Cmax Tmax Drug ng/mL Day 210 240 300 360 420 480 540600 660 720 N (ng/mL) (hr) S7F Mean 1 22 14 6 3 1 0 0 0 0 0 30 498 0.61S7F Min 1 0 0 0 0 0 0 0 0 0 0 30 140 0.25 S7F Max 1 76 46 23 18 10 14 05 7 6 30 1090 1.50 S7F Mean 7 90 65 38 22 13 7 4 3 1 1 30 680 0.82 S7FMin 7 10 6 0 0 0 0 0 0 0 0 30 228 0.25 S7F Max 7 362 297 196 143 91 6142 28 18 13 30 1530 1.50 Pr Mean 1 44 28 12 6 3 1 0 0 0 0 30 328 1.41 PrMin 1 8 0 0 0 0 0 0 0 0 0 30 101 0.75 Pr Max 1 163 105 51 25 13 8 0 0 65 30 794 3.00 Pr Mean 7 104 86 47 26 15 8 5 3 1 1 30 487 1.30 Pr Min 714 0 0 0 0 0 0 0 0 0 30 170 0.50 Pr Max 7 308 456 167 122 73 65 39 25 1811 30 1220 2.50

Example 15A Formulation of SAN-7E (40 mg Omeprazole Capsules)

A 1300 kg lot of 40 mg omeprazole capsules was manufactured under cGMPconditions. The formulation is set forth in Table 15A, below:

TABLE 15A Amount Required % for 1300 kg Ingredient Weight mg/CapsuleBatch (kg) Omeprazole, USP 3.5% 40.8 mg/cap 45.7 kg Sodium Bicarbonate,USP 93.2 1100 1232 #2 Croscarmellose Sodium, NF 1.5 30 33.6 MagnesiumStearate, NF 0.8 10 11.2 Totals 100 1160.4 1300

The following ingredients were added to a tote (tote #1) in thefollowing order: Sodium bicarbonate (about 25% of total), omeprazoleUSP, sodium bicarbonate (about 25% of total). The contents of tote #1were then charged into a 60 ft³ V-blender through a Comil® powder millequipped with a 16 mesh equivalent screen, operating the powder screenat a speed setting of high (800 rpm). The contents were mixed for 5minutes at 8 rpm. About 25% of the total amount of sodium bicarbonatewas then charged into a tote (tote #2). Then the contents of theV-blender were charged into tote #2. The contents of tote #2 were thenpassed through a Comil® powder mill equipped with a 16 mesh equivalentscreen at a speed setting of high (800 rpm).

Next, croscarmellose sodium and the remaining amount of sodiumbicarbonate were charged into tote #1. The contents of tote #1 were thenpassed through a Comil® powder mill equipped with a 16 mesh equivalentscreen at a speed setting of high (800 rpm) and charged into theV-blender. The mixture was then blended for 15 minutes a 8 rpm. Thenmagnesium stearate was screened through a #30 mesh hand screen andcharged into the V-blender. The resulting mixture was then blended for 3minutes at 8 rpm. The contents of the V-blender were then dischargedinto labeled containers lined with inner clear polyethylene bagoverwrapped with an outer black polyethylene bag. The resulting mixturewas encapsulated on a H&K 1200® dosing disc/tamping pin-typeencapsulator using hard gelatin capsules size #00.

Example 15B Clinical Trial

A clinical trial was conducted in order to compare the pharmacokineticprofile of a 40 mg omeprazole capsule according to the present inventionwith Prilosec® 40 mg delayed release capsules. SAN-7E 40 mg capsulesaccording to the invention were formulated as in Example 7B, above. Theresults of these clinical trials are discussed below and are depictedgraphically in FIGS. 16, 18, 19, 21, 22 and 23.

Trial objectives, design, pharmacokinetic and pharmacodynamic endpoints,design rationale, treatments administered, schedule of events,pharmacokinetic sampling, analytical methods and parameters, measurementof gastric pH, pharmacodynamic parameters and methodology,pharmacokinetic statistical and analytical plan are the same as inExample 14 above with the exception of use with SAN-7E Capsules 40 mgand Prilosec 40 mg instead of 20 mg of each drug. The capsules areprepared by blending the PPI and homogeneously blending with othercomponents shown in Table 15A.

Number of Subjects (Planned and Analyzed):

Thirty-six subjects were dosed and 30 subjects complete 7 days of dosingin each period of the trial. Thirty-five subjects were included in thepharmacokinetic analysis and 34 subjects were included in thepharmacodynamic analysis for Doses 1 and 7. Eighteen subjects wereincluded in the post-meal (Day 8) versus pre-meal (Day 7) analysis.

Duration of Treatment:

Including screening, subjects participated in this trial for up to 41days.

Pharmacokinetic Results

Pharmacokinetic results are presented in the Table 15.B. and FIGS. 16,18, 19, 21, 22 and 23.

Pharmacokinetic Conclusions

After the first dose and at steady state (Day 7), SAN-7E Capsules 40 mgwere equivalent to Prilosec 40 mg with respect to [AUC(0-inf)] (theprimary pharmacokinetic endpoint). The 2 treatments were not equivalentwith respect to Cmax on Days 1 and 7 with the percent mean ratio of 149%on Day 1 and 117% on Day 7. The Tmax was shorter for theimmediate-release product on Days 1 and 7 (p<0.001).

Pharmacodynamic Conclusions

On Day 7 of dosing, SAN-7E Capsules 40 mg were found equivalent toPrilosec 40 mg with regard to the primary pharmacodynamic endpoint,percent decrease from baseline in integrated gastric acidity over 24hours. SAN-7E 40 mg and Prilosec 40 mg both decreased integrated gastricacidity by 74% and 80%, respectively, from Baseline at Day 7.

TABLE 15.A SAN-7E Capsules Composition, 40 mg Omeprazole QuantityIngredient (40 mg) Omeprazole 40.8 mg* Sodium Bicarbonate 1100 mgCROSCARMELLOSE SODIUM 30 mg Magnesium Stearate 10 mg Gelatin Capsule 1shell Total Weight/Unit 1180 mg *Includes a 2% omeprazole overage in theblend manufacture that assures label claim amount of omeprazole in thefinal product.

TABLE 15.B 40 mg PK Summary for Day 1 and 7. (Drug: S7E = SAN-7E; Pr =Prilosec ® 40 mg.) Interval (minutes) Drug ng/mL Day 0 5 10 15 20 30 4560 90 120 150 180 S7E Mean 1 0 0 46 237 535 842 840 709 545 338 248 193S7E Min 1 0 0 0 0 0 24 116 127 0 19 14 7 S7E Max 1 0 12 703 1730 23102420 2420 2120 2000 1570 1450 1210 S7E Mean 7 3 3 63 202 398 949 11151104 1083 747 585 463 S7E Min 7 0 0 0 0 0 13 32 37 262 0 74 42 S7E Max 796 82 1900 3420 2960 3020 2420 2380 2350 1980 1850 1620 Pr Mean 1 0 0 00 3 71 195 408 793 546 369 259 Pr Min 1 0 0 0 0 0 0 0 0 111 59 23 10 PrMax 1 0 0 0 0 58 1800 1140 1580 2650 2100 1650 1350 Pr Mean 7 1 1 1 2 20171 456 639 1217 969 725 606 Pr Min 7 0 0 0 0 0 0 0 0 12 119 116 67 PrMax 7 16 14 14 19 392 1420 2110 2230 2950 2370 1770 1620 Cmax Tmax Drugng/mL Day 210 240 300 360 420 480 540 600 660 720 N (ng/mL) (hr) S7EMean 1 152 125 86 60 41 30 22 16 12 9 35 1154 0.56 S7E Min 1 5 0 0 0 0 00 0 0 0 35 255 0.25 S7E Max 1 1140 1080 871 707 520 457 362 294 230 18635 2420 1.50 S7E Mean 7 393 323 249 183 131 94 74 53 37 28 35 1526 0.97S7E Min 7 27 14 0 0 0 0 0 0 0 0 35 437 0.25 S7E Max 7 1570 1570 13501190 1060 736 636 572 418 386 35 3420 3.50 Pr Mean 1 208 164 114 77 4538 27 20 17 12 35 888 1.51 Pr Min 1 0 6 0 0 0 0 0 0 0 0 35 119 0.50 PrMax 1 1250 1140 919 592 295 422 310 270 217 174 35 2650 2.50 Pr Mean 7466 397 264 188 131 95 65 46 34 22 35 1344 1.51 Pr Min 7 30 20 7 0 0 000 0 0 0 35 234 0.50 Pr Max 7 1420 1260 1000 801 549 435 310 240 199 13335 2950 2.50The number of patients who completed the post-meal portion of the studywas 18. The following table summarizes the pharmacokinetic parametersfor the pre- and post-meal dosing of 40 mg omeprazole immediate releasecapsules.

TABLE 15.C Summary of Post-meal (Day 8) and Pre-meal (Day 7) PlasmaOmeprazole Pharmacokinetic Parameters for Immediate Release Capsules(SAN-7E) Plasma Omeprazole SAN-7E SAN-7E (Post-meal) (Pre-meal)Parameter n Mean S.D. n Mean S.D. Cmax (ng/mL) 18 1026 645.6 18 1646771.4 Tmax (hr) 18 1.74 1.27 18 0.93 0.74 AUC (0–t)(ng * hr/mL) 18 32212349 18 3976 2592 AUC(0–inf)(ng * hr/mL) 18 3221 2488 18 4071 2721 T½(hr) 18 1.38 0.66 18 1.38 0.66 kel (1/hr) 18 0.61 0.26 18 0.61 0.27 In(Cmax) 18 6.70 0.79 18 7.28 0.54 In[AUC(0–t)] 18 7.76 0.90 18 8.01 0.84IN[AUC(0–inf)] 18 7.78 0.91 18 8.03 0.85

Example 16 Powder for Suspension

Following procedures similar to those set forth in Examples 14 and 15,above, 20 and 40 mg omeprazole immediate release powders for suspensionwere prepared and tested in subjects. The powder compositions tested areset forth in the following tables 16A and 16B.

TABLE 16A Omeprazole Powder for Suspension 20 mg per dose OmeprazoleImmediate Release Powder Ingredient 20 mg per dose Omeprazole,Micronized USP 0.021 Sodium Bicarbonate 1.680 Xanthan Gum 0.039 Sucrose2.000 Xylitol 2.000 Crystalline Sucralose 0.080 Peppermint Flavor, ManeF94249 0.011 Peach flavor #57.695/AP 05.51 0.030 Totals 5.861

TABLE 16B Omeprazole Powder for Suspension 40 mg per dose OmeprazoleImmediate Release Powder Ingredient 40 mg per dose Omeprazole,Micronized USP 0.042 Sodium Bicarbonate 1.680 Xanthan Gum 0.039 Sucrose2.000 Xylitol 2.000 Crystalline Sucralose 0.080 Peppermint Flavor, ManeF94249 0.011 Peach flavor #57.695/AP 05.51 0.030 Totals 5.882

The results of these clinical trials are set forth in FIGS. 16-23.

Many modifications, equivalents, and variations of the present inventionare possible in light of the above teachings, therefore, it is to beunderstood that within the scope of the appended claims, the inventionmay be practiced other than as specifically described.

What is claimed is:
 1. A pharmaceutical formulation in a single capsuledosage form consisting of: (a) about 10 mgs to about 100 mgs of at leastone micronized bicyclic aryl-imidazole acid-labile proton pumpinhibitor; (b) at least one antacid, wherein the antacid comprises about400 mgs to about 1400 mgs of sodium bicarbonate; (c) about 2 wt-% toabout 5 wt-% of a disintegrant; and (d) about 0.5 wt-% to about 3 wt-%of Magnesium Stearate wherein upon oral administration of the capsule toa fasted human subject, a T_(max) of the proton pump inhibitor isobtained within 60 minutes after administration on day 1; and an initialserum concentration of the proton pump inhibitor is greater than 300ng/ml within 45 minutes after administration.
 2. The pharmaceuticalformulation according to claim 1, wherein the proton pump inhibitor isomeprazole, esomeprazole or lansoprazole, or a salt thereof.
 3. Thepharmaceutical formulation according to claim 1, wherein the antacidfurther comprises potassium bicarbonate, sodium carbonate, calciumcarbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate,aluminum hydroxide, or mixtures thereof; and the total amount of antacidpresent in the capsule is about 10 mEq.
 4. The pharmaceuticalformulation according to claim 1, wherein the sodium bicarbonate ispresent in an amount of at least 800 mgs.
 5. The pharmaceuticalformulation according to claim 1, wherein the disintegrant iscroscarmellose sodium and is present in an amount of about 3 wt-%. 6.The pharmaceutical formulation according to claim 1, wherein thedisintegrant is present in an amount of about 3 wt-% to about 5 wt-%. 7.The pharmaceutical formulation of claim 1, wherein T_(max) of the protonpump inhibitor on day 7 is obtained within 60 minutes after oraladministration of the capsule to the subject.
 8. The pharmaceuticalformulation according to claim 1, wherein the average C_(max) of theproton pump inhibiting agent is less than 1250 ng/ml after oraladministration of the capsule to the subject.
 9. A pharmaceuticalformulation in a single capsule oral dosage form consisting of: (a)micronized omeprazole or a salt thereof in an amount of about 20 mgs orabout 40 mgs; (b) about 800 mgs to about 1400 mgs of sodium bicarbonate(NaHCO₃); (c) about 2 wt-% to about 8 wt-% of a disintegrant; and (d)about 0.5 wt-% to about 3 wt-% of Magnesium Stearate.
 10. Thepharmaceutical composition of claim 9, wherein: (a) the NaHCO₃ ispresent in an amount of between 1000 mgs and 1300 mgs; and (b) thedisintegrant is croscarmellose sodium and is present in an amount ofabout 3 wt-% to about 5 wt-%; wherein upon oral administration of thecapsule to a fasted human subject, a T_(max) of the proton pumpinhibitor is obtained within 60 minutes after administration on day 1.11. A method of inhibiting a gastric acid related gastrointestinaldisorder in a subject comprising administering one or more capsules of asingle capsule oral dosage form to a human subject in need thereof, thesingle capsule oral dosage form consisting of: (a) about 10 mgs to about100 mgs of at least one micronized bicyclic aryl-imidazole acid-labileproton pump inhibitor; (b) an antacid, wherein the antacid comprisesabout 400 mgs to about 1400 mgs of sodium bicarbonate (NaHCO₃); (c)about 2 wt-% to about 5 wt-% of a disintegrant; and (d) about 0.5 wt-%to about 3 wt-% of Magnesium Stearate wherein upon oral administrationof the capsule to a fasted human subject, a Tmax of the proton pumpinhibitor is obtained within 60 minutes after administration on day 1.